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Carvalho LDA, Alves VS, Coutinho-Silva R, Savio LEB. G protein-coupled purinergic P2Y receptors in infectious diseases. Pharmacol Ther 2025; 267:108796. [PMID: 39814144 DOI: 10.1016/j.pharmthera.2025.108796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/24/2024] [Accepted: 01/03/2025] [Indexed: 01/18/2025]
Abstract
The purinergic P2Y receptors comprise eight G-coupled receptor (GPCR) subtypes already identified (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12-14). P2Y receptor physiological agonists are extracellular purine and pyrimidine nucleotides such as ATP (Adenosine triphosphate), ADP (Adenosine diphosphate), UTP (Uridine triphosphate), UDP (Uridine diphosphate), and UDP-glucose. These receptors are expressed in almost all cells. P2Y receptors are found in immune cells, such as macrophages, neutrophils, mast cells, dendritic cells, and lymphocytes. P2Y receptors play essential roles in inflammation and are involved in several cell processes, including efferocytosis, phagocytosis, chemotaxis, degranulation, killing pathogens, cytokine production, and platelet aggregation. These processes underpin immune responses against pathogens. Therefore, here we discuss P2Y receptor pharmacology and mechanisms triggered by the activation of these receptors in virus, bacteria, and parasite infections. In addition, we highlight the therapeutical potential of P2Y receptors for developing new pharmacological strategies to modulate inflammation and disease outcomes in pathogen infections.
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Affiliation(s)
- Letícia de Almeida Carvalho
- Laboratório de Neuroimunologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vinícius Santos Alves
- Laboratório de Neuroimunologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Robson Coutinho-Silva
- Laboratório de Imunofisiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Luiz Eduardo Baggio Savio
- Laboratório de Neuroimunologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
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Golenkina EA, Viryasova GM, Galkina SI, Iakushkina IV, Gaponova TV, Romanova YM, Sud’ina GF. ATP and Formyl Peptides Facilitate Chemoattractant Leukotriene-B4 Synthesis and Drive Calcium Fluxes, Which May Contribute to Neutrophil Swarming at Sites of Cell Damage and Pathogens Invasion. Biomedicines 2024; 12:1184. [PMID: 38927391 PMCID: PMC11201259 DOI: 10.3390/biomedicines12061184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/16/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Here, we demonstrate that human neutrophil interaction with the bacterium Salmonella typhimurium fuels leukotriene B4 synthesis induced by the chemoattractant fMLP. In this work, we found that extracellular ATP (eATP), the amount of which increases sharply during tissue damage, can effectively regulate fMLP-induced leukotriene B4 synthesis. The vector of influence strongly depends on the particular stage of sequential stimulation of neutrophils by bacteria and on the stage at which fMLP purinergic signaling occurs. Activation of 5-lipoxygenase (5-LOX), key enzyme of leukotriene biosynthesis, depends on an increase in the cytosolic concentration of Ca2+. We demonstrate that eATP treatment prior to fMLP, by markedly reducing the amplitude of the fMLP-induced Ca2+ transient jump, inhibits leukotriene synthesis. At the same time, when added with or shortly after fMLP, eATP effectively potentiates arachidonic acid metabolism, including by Ca2+ fluxes stimulation. Flufenamic acid, glibenclamide, and calmodulin antagonist R24571, all of which block calcium signaling in different ways, all suppressed 5-LOX product synthesis in our experimental model, indicating the dominance of calcium-mediated mechanisms in eATP regulatory potential. Investigation into the adhesive properties of neutrophils revealed the formation of cell clusters when adding fMLP to neutrophils exposed to the bacterium Salmonella typhimurium. eATP added simultaneously with fMLP supported neutrophil polarization and clustering. A cell-derived chemoattractant such as leukotriene B4 plays a crucial role in the recruitment of additional neutrophils to the foci of tissue damage or pathogen invasion, and eATP, through the dynamics of changes in [Ca2+]i, plays an important decisive role in fMLP-induced leukotrienes synthesis during neutrophil interactions with the bacterium Salmonella typhimurium.
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Affiliation(s)
- Ekaterina A. Golenkina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia; (E.A.G.); (G.M.V.); (S.I.G.); (I.V.I.)
| | - Galina M. Viryasova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia; (E.A.G.); (G.M.V.); (S.I.G.); (I.V.I.)
| | - Svetlana I. Galkina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia; (E.A.G.); (G.M.V.); (S.I.G.); (I.V.I.)
| | - Iuliia V. Iakushkina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia; (E.A.G.); (G.M.V.); (S.I.G.); (I.V.I.)
| | - Tatjana V. Gaponova
- National Research Center for Hematology, Russia Federation Ministry of Public Health, 125167 Moscow, Russia;
| | - Yulia M. Romanova
- Department of Genetics and Molecular Biology, Gamaleya National Research Centre of Epidemiology and Microbiology, 123098 Moscow, Russia;
| | - Galina F. Sud’ina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia; (E.A.G.); (G.M.V.); (S.I.G.); (I.V.I.)
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Zhang HL, Doblin S, Zhang ZW, Song ZJ, Dinesh B, Tabana Y, Saad DS, Adam Ahmed Adam M, Wang Y, Wang W, Zhang HL, Wu S, Zhao R, Khaled B. Elucidating the molecular basis of ATP-induced cell death in breast cancer: Construction of a robust prognostic model. World J Clin Oncol 2024; 15:208-242. [PMID: 38455130 PMCID: PMC10915939 DOI: 10.5306/wjco.v15.i2.208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/10/2023] [Accepted: 01/12/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Breast cancer is a multifaceted and formidable disease with profound public health implications. Cell demise mechanisms play a pivotal role in breast cancer pathogenesis, with ATP-triggered cell death attracting mounting interest for its unique specificity and potential therapeutic pertinence. AIM To investigate the impact of ATP-induced cell death (AICD) on breast cancer, enhancing our understanding of its mechanism. METHODS The foundational genes orchestrating AICD mechanisms were extracted from the literature, underpinning the establishment of a prognostic model. Simultaneously, a microRNA (miRNA) prognostic model was constructed that mirrored the gene-based prognostic model. Distinctions between high- and low-risk cohorts within mRNA and miRNA characteristic models were scrutinized, with the aim of delineating common influence mechanisms, substantiated through enrichment analysis and immune infiltration assessment. RESULTS The mRNA prognostic model in this study encompassed four specific mRNAs: P2X purinoceptor 4, pannexin 1, caspase 7, and cyclin 2. The miRNA prognostic model integrated four pivotal miRNAs: hsa-miR-615-3p, hsa-miR-519b-3p, hsa-miR-342-3p, and hsa-miR-324-3p. B cells, CD4+ T cells, CD8+ T cells, endothelial cells, and macrophages exhibited inverse correlations with risk scores across all breast cancer subtypes. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis revealed that genes differentially expressed in response to mRNA risk scores significantly enriched 25 signaling pathways, while miRNA risk scores significantly enriched 29 signaling pathways, with 16 pathways being jointly enriched. CONCLUSION Of paramount significance, distinct mRNA and miRNA signature models were devised tailored to AICD, both potentially autonomous prognostic factors. This study's elucidation of the molecular underpinnings of AICD in breast cancer enhances the arsenal of potential therapeutic tools, offering an unparalleled window for innovative interventions. Essentially, this paper reveals the hitherto enigmatic link between AICD and breast cancer, potentially leading to revolutionary progress in personalized oncology.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Sandai Doblin
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Babu Dinesh
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Dahham Sabbar Saad
- Department of Science, University of Technology and Applied Sciences Rustaq, Rustaq 10 P.C. 329, Oman
| | - Mowaffaq Adam Ahmed Adam
- Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States
| | - Yong Wang
- Department of Pathology Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Wei Wang
- College of Acupuncture-moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Long Zhang
- Universiti Sains Malaysia, Advanced Medical and Dental Institute, Penang 13200, Malaysia
| | - Sen Wu
- Department of Biomedical Science, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Barakat Khaled
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
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Acuña-Castillo C, Escobar A, García-Gómez M, Bachelet VC, Huidobro-Toro JP, Sauma D, Barrera-Avalos C. P2X7 Receptor in Dendritic Cells and Macrophages: Implications in Antigen Presentation and T Lymphocyte Activation. Int J Mol Sci 2024; 25:2495. [PMID: 38473744 DOI: 10.3390/ijms25052495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/15/2024] [Accepted: 01/24/2024] [Indexed: 03/14/2024] Open
Abstract
The P2X7 receptor, a member of the P2X purinergic receptor family, is a non-selective ion channel. Over the years, it has been associated with various biological functions, from modulating to regulating inflammation. However, its emerging role in antigen presentation has captured the scientific community's attention. This function is essential for the immune system to identify and respond to external threats, such as pathogens and tumor cells, through T lymphocytes. New studies show that the P2X7 receptor is crucial for controlling how antigens are presented and how T cells are activated. These studies focus on antigen-presenting cells, like dendritic cells and macrophages. This review examines how the P2X7 receptor interferes with effective antigen presentation and activates T cells and discusses the fundamental mechanisms that can affect the immune response. Understanding these P2X7-mediated processes in great detail opens up exciting opportunities to create new immunological therapies.
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Affiliation(s)
- Claudio Acuña-Castillo
- Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9160000, Chile
- Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9160000, Chile
| | - Alejandro Escobar
- Laboratorio Biología Celular y Molecular, Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago 8380000, Chile
| | - Moira García-Gómez
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile
| | - Vivienne C Bachelet
- Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago 9160000, Chile
| | - Juan Pablo Huidobro-Toro
- Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9160000, Chile
| | - Daniela Sauma
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile
- Centro Ciencia & Vida, Av. Del Valle Norte 725, Huechuraba 8580000, Chile
| | - Carlos Barrera-Avalos
- Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9160000, Chile
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Wang Y, Wakelam MJO, Bankaitis VA, McDermott MI. The wide world of non-mammalian phospholipase D enzymes. Adv Biol Regul 2024; 91:101000. [PMID: 38081756 DOI: 10.1016/j.jbior.2023.101000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 11/15/2023] [Indexed: 02/25/2024]
Abstract
Phospholipase D (PLD) hydrolyses phosphatidylcholine (PtdCho) to produce free choline and the critically important lipid signaling molecule phosphatidic acid (PtdOH). Since the initial discovery of PLD activities in plants and bacteria, PLDs have been identified in a diverse range of organisms spanning the taxa. While widespread interest in these proteins grew following the discovery of mammalian isoforms, research into the PLDs of non-mammalian organisms has revealed a fascinating array of functions ranging from roles in microbial pathogenesis, to the stress responses of plants and the developmental patterning of flies. Furthermore, studies in non-mammalian model systems have aided our understanding of the entire PLD superfamily, with translational relevance to human biology and health. Increasingly, the promise for utilization of non-mammalian PLDs in biotechnology is also being recognized, with widespread potential applications ranging from roles in lipid synthesis, to their exploitation for agricultural and pharmaceutical applications.
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Affiliation(s)
- Y Wang
- Department of Cell Biology & Genetics, Texas A&M Health Science Center, College Station, TX, 77843, USA; Department of Microbiology, University of Washington, Seattle, WA98109, USA
| | - M J O Wakelam
- Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom
| | - V A Bankaitis
- Department of Cell Biology & Genetics, Texas A&M Health Science Center, College Station, TX, 77843, USA; Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843, USA; Department of Chemistry, Texas A&M University, College Station, TX, 77843, USA
| | - M I McDermott
- Department of Cell Biology & Genetics, Texas A&M Health Science Center, College Station, TX, 77843, USA.
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6
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Zheng YW, Wang M, Xie JW, Chen R, Wang XT, He Y, Yang TC, Liu LL, Lin LR. Recombinant Treponema pallidum protein Tp47 promoted the phagocytosis of macrophages by activating NLRP3 inflammasome induced by PKM2-dependent glycolysis. J Eur Acad Dermatol Venereol 2023; 37:2067-2079. [PMID: 37247195 DOI: 10.1111/jdv.19231] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 05/05/2023] [Indexed: 05/30/2023]
Abstract
BACKGROUND Glycolysis is a critical pathway in cellular glucose metabolism that provides energy and participates in immune responses. However, whether glycolysis is involved in NOD-like receptor family protein 3 (NLRP3) inflammasome activation and phagocytosis of macrophages in response to Treponema pallidum infection remains unclear. OBJECTIVES To investigate the role of glycolysis in activating the NLRP3 inflammasome for regulating phagocytosis in macrophages in response to T. pallidum protein Tp47 and its associated mechanisms. METHODS Interactions between activation of the NLRP3 inflammasome and phagocytosis and the role of glycolysis in Tp47-treated macrophages were investigated through experiments on peritoneal macrophages and human monocytic cell line-derived macrophages. RESULTS Activation of phagocytosis and NLRP3 inflammasome were observed in Tp47-treated macrophages. Treatment with NLRP3 inhibitor MCC950 or si-NLRP3 attenuated Tp47-induced phagocytosis. Glycolysis and glycolytic capacity were enhanced by Tp47 stimulation in macrophages, and a change in the levels of glycolytic metabolites (phosphoenolpyruvate, citrate and lactate) was induced by Tp47 in macrophages. Inhibition of glycolysis with 2-deoxy-D-glucose, a glycolysis inhibitor, decreased the activation of NLRP3. Expression of M2 isoform of pyruvate kinase (PKM2), an enzyme catalysing a rate-limiting reaction in the glycolytic pathway, was upregulated in Tp47-stimulated macrophages. Inhibition of PKM2 with shikonin or si-PKM2 decreased glycolysis and NLRP3 activation. CONCLUSION Tp47 promotes phagocytosis in macrophages by activating the NLRP3 inflammasome, which is induced by the enhancement of PKM2-dependent glycolysis.
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Affiliation(s)
- Y-W Zheng
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - M Wang
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - J-W Xie
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - R Chen
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - X-T Wang
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - Y He
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - T-C Yang
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - L-L Liu
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
| | - L-R Lin
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, China
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Gupta PK, Jahagirdar P, Tripathi D, Devarajan PV, Kulkarni S. Macrophage targeted polymeric curcumin nanoparticles limit intracellular survival of Mycobacterium tuberculosis through induction of autophagy and augment anti-TB activity of isoniazid in RAW 264.7 macrophages. Front Immunol 2023; 14:1233630. [PMID: 37583694 PMCID: PMC10424441 DOI: 10.3389/fimmu.2023.1233630] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/12/2023] [Indexed: 08/17/2023] Open
Abstract
Rapid emergence of antibiotic resistance in tuberculosis has left us with limited resources to treat and manage multi drug resistant (MDR) cases of tuberculosis, prompting the development of novel therapeutics. Mycobacterium tuberculosis (MTB) perturbs the host protective pathways for its survival, therefore host directed therapeutic (HDT) interventions offer an attractive alternative strategy. Curcumin (CMN), the principle curcuminoid from Curcuma longa is known to have anti-TB activity against MDR strains of MTB in macrophages. We discovered that treatment of CMN induced autophagy in uninfected and MTB infected macrophages which was evident by conversion of LC3-I to LC3-II and degradation of p62. Inhibition of autophagy by a pharmacological inhibitor 3-MA resulted in significant inhibition of intracellular killing activity of CMN, suggesting the involvement of autophagy in intracellular clearance of MTB. Moreover, annexin v-FITC/PI staining data suggested induction of apoptosis in uninfected and MTB infected macrophages post CMN treatment. This finding was further corroborated by up-regulated expression of pro-apoptotic proteins, Bax, cleaved caspase-3 and PARP and diminished expression of anti-apoptotic protein Bcl-2 as evaluated by immunoblotting. Using GFP-MTB H37Rv and Lysotracker Red staining we demonstrated co-localization of GFP-MTB H37Rv containing phagosome to lysosome after CMN treatment, indicating enhanced phagosome lysosome fusion. Due to poor bioavailability of CMN, its clinical use is limited, therefore to overcome this issue, CMN was encapsulated in Poly(lactic-co-glycolic) acid (PLGA) shell, resulting in polymeric CMN nano particles (ISCurNP). Flow cytometric evaluation suggested >99% uptake of ISCurNP after 3h of treatment. In BALB/c mice, oral dose of ISCurNP resulted in 6.7-fold increase in the bioavailability compared to free CMN. Moreover, ISCurNP treatment resulted in significant decrease in the intracellular survival of MTB H37Rv through induction of autophagy. Adjunct action of ISCurNP and CMN in combination with isoniazid (INH) revealed >99% decrease in intracellular survival of MTB in macrophage as compared to ISCurNP, CMN or INH alone. In conclusion, our findings suggest the role of ISCurNP as novel host directed formulation to combat both sensitive and MDR strains of MTB by induction of autophagy.
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Affiliation(s)
- Pramod Kumar Gupta
- Tuberculosis Immunology and Immunoassay Development Section, Radiation Medicine Centre, Bhabha Atomic Research Centre, Mumbai, India
- Faculty of Life Science, Homi Bhabha National Institute, Mumbai, India
| | - Priyanka Jahagirdar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Devavrat Tripathi
- Tuberculosis Immunology and Immunoassay Development Section, Radiation Medicine Centre, Bhabha Atomic Research Centre, Mumbai, India
| | - Padma V. Devarajan
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Savita Kulkarni
- Tuberculosis Immunology and Immunoassay Development Section, Radiation Medicine Centre, Bhabha Atomic Research Centre, Mumbai, India
- Faculty of Life Science, Homi Bhabha National Institute, Mumbai, India
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Kumar A, Naik L, Patel S, Das M, Nayak DK, Mishra A, Mishra A, Singh R, Behura A, Dhiman R. Ac-93,253 inhibits intracellular growth of mycobacteria in human macrophages by inducing apoptosis in mitochondrial-dependent manner. Biochim Biophys Acta Gen Subj 2023:130425. [PMID: 37423324 DOI: 10.1016/j.bbagen.2023.130425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 04/13/2023] [Accepted: 07/04/2023] [Indexed: 07/11/2023]
Abstract
Recent studies suggest that apoptosis in macrophages plays a significant role in host defence against intracellular pathogens like viruses, fungi, protozoan, and bacteria, including Mycobacterium tuberculosis (M. tb). It is still unclear if micromolecules inducing apoptosis could be an attractive approach to combat the intracellular burden of M. tb. Hence, the present study has investigated the anti-mycobacterial effect of apoptosis mediated through phenotypic screening of micromolecules. Through MTT and trypan blue exclusion assay, 0.5 μM of Ac-93,253 was found to be non-cytotoxic even after 72 h of treatment in phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. Significant regulation in the expression of various pro-apoptotic genes like Bcl-2, Bax, and Bad and the cleaved caspase 3 was observed upon treatment with a non-cytotoxic dose of Ac-93,253. Ac-93,253 treatment also leads to DNA fragmentation and increased phosphatidylserine accumulation in the plasma membrane's outer leaflet. Further, Ac-93,253 also effectively reduced the growth of mycobacteria in infected macrophages, Z-VAD-FMK a broad-range apoptosis inhibitor significantly brought back the mycobacterial growth in Ac-93,253 treated macrophages. These findings suggest apoptosis may be the probable effector response through which Ac-93,253 manifests its anti-mycobacterial property.
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Affiliation(s)
- Ashish Kumar
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Lincoln Naik
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Salina Patel
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Mousumi Das
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Dev Kiran Nayak
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Abtar Mishra
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India
| | - Ramandeep Singh
- Tuberculosis Research Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3(rd) Milestone, Faridabad-Gurugram Expressway, PO Box # 4, Faridabad 121001, Haryana, India
| | - Assirbad Behura
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
| | - Rohan Dhiman
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
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Santiago-Carvalho I, Banuelos A, Borges da Silva H. Tissue- and temporal-specific roles of extracellular ATP on T cell metabolism and function. IMMUNOMETABOLISM (COBHAM, SURREY) 2023; 5:e00025. [PMID: 37143525 PMCID: PMC10150631 DOI: 10.1097/in9.0000000000000025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 04/13/2023] [Indexed: 05/06/2023]
Abstract
The activation and function of T cells is fundamental for the control of infectious diseases and cancer, and conversely can mediate several autoimmune diseases. Among the signaling pathways leading to T cell activation and function, the sensing of extracellular adenosine triphosphate (eATP) has been recently appreciated as an important component. Through a plethora of purinergic receptors, most prominently P2RX7, eATP sensing can induce a wide variety of processes in T cells, such as proliferation, subset differentiation, survival, or cell death. The downstream roles of eATP sensing can vary according to (a) the T cell subset, (b) the tissue where T cells are, and (c) the time after antigen exposure. In this mini-review, we revisit the recent findings on how eATP signaling pathways regulate T-cell immune responses and posit important unanswered questions on this field.
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Affiliation(s)
| | - Alma Banuelos
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ, USA
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Schäfer W, Stähler T, Pinto Espinoza C, Danquah W, Knop JH, Rissiek B, Haag F, Koch-Nolte F. Origin, distribution, and function of three frequent coding polymorphisms in the gene for the human P2X7 ion channel. Front Pharmacol 2022; 13:1033135. [DOI: 10.3389/fphar.2022.1033135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/28/2022] [Indexed: 11/20/2022] Open
Abstract
P2X7, an ion channel gated by extracellular ATP, is widely expressed on the plasma membrane of immune cells and plays important roles in inflammation and apoptosis. Several single nucleotide polymorphisms have been identified in the human P2RX7 gene. In contrast to other members of the P2X family, non-synonymous polymorphisms in P2X7 are common. Three of these occur at overall frequencies of more than 25% and affect residues in the extracellular “head”-domain of P2X7 (155 Y/H), its “lower body” (270 R/H), and its “tail” in the second transmembrane domain (348 T/A). Comparison of the P2X7 orthologues of human and other great apes indicates that the ancestral allele is Y—R—T (at 155–270–348). Interestingly, each single amino acid variant displays lower ATP-sensitivity than the ancestral allele. The originally published reference sequence of human P2X7, often referred to as “wildtype,” differs from the ancestral allele at all three positions, i.e. H—H—A. The 1,000 Genome Project determined the sequences of both alleles of 2,500 human individuals, including roughly 500 persons from each of the five major continental regions. This rich resource shows that the ancestral alleles Y155, R270, and T348 occur in all analyzed human populations, albeit at strikingly different frequencies in various subpopulations (e.g., 25%–59% for Y155, 59%–77% for R270, and 13%–47% for T348). BLAST analyses of ancient human genome sequences uncovered several homozygous carriers of variant P2X7 alleles, possibly reflecting a high degree of inbreeding, e.g., H—R—T for a 50.000 year old Neanderthal, H—R—A for a 24.000 year old Siberian, and Y—R—A for a 7,000 year old mesolithic European. In contrast, most present-day individuals co-express two copies of P2X7 that differ in one or more amino acids at positions 155, 270, and 348. Our results improve the understanding of how P2X7 structure affects its function and suggest the importance of considering P2X7 variants of participants when designing clinical trials targeting P2X7.
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11
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Alberto AVP, Ferreira NCDS, Bonavita AGC, Nihei OK, de Farias FP, Bisaggio RDC, de Albuquerque C, Savino W, Coutinho‐Silva R, Persechini PM, Alves LA. Physiologic roles of P2 receptors in leukocytes. J Leukoc Biol 2022; 112:983-1012. [PMID: 35837975 PMCID: PMC9796137 DOI: 10.1002/jlb.2ru0421-226rr] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/13/2022] [Indexed: 01/01/2023] Open
Abstract
Since their discovery in the 1970s, purinergic receptors have been shown to play key roles in a wide variety of biologic systems and cell types. In the immune system, purinergic receptors participate in innate immunity and in the modulation of the adaptive immune response. In particular, P2 receptors, which respond to extracellular nucleotides, are widely expressed on leukocytes, causing the release of cytokines and chemokines and the formation of inflammatory mediators, and inducing phagocytosis, degranulation, and cell death. The activity of these receptors is regulated by ectonucleotidases-expressed in these same cell types-which regulate the availability of nucleotides in the extracellular environment. In this article, we review the characteristics of the main purinergic receptor subtypes present in the immune system, focusing on the P2 family. In addition, we describe the physiologic roles of the P2 receptors already identified in leukocytes and how they can positively or negatively modulate the development of infectious diseases, inflammation, and pain.
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Affiliation(s)
- Anael Viana Pinto Alberto
- Laboratory of Cellular Communication, Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de JaneiroRJBrazil
| | | | | | - Oscar Kenji Nihei
- Center of Education and LetterState University of the West of ParanáFoz do IguaçuPRBrazil
| | | | - Rodrigo da Cunha Bisaggio
- Laboratory of Cellular Communication, Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de JaneiroRJBrazil,Federal Institute of Education, Science, and Technology of Rio de JaneiroRio de JaneiroRJBrazil
| | | | - Wilson Savino
- Laboratory on Thymus Research, Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de JaneiroRJBrazil,Brazilian National Institute of Science and Technology on NeuroimmunomodulationRio de Janeiro Research Network on NeuroinflammationRio de JaneiroRJBrazil
| | - Robson Coutinho‐Silva
- Laboratory of Immunophysiology, Carlos Chagas Filho Biophysics InstituteFederal University of Rio de JaneiroRio de JaneiroRJBrazil
| | - Pedro Muanis Persechini
- Laboratory of Immunobiophysics, Carlos Chagas Filho Biophysics InstituteFederal University of Rio de JaneiroRio de JaneiroRJBrazil
| | - Luiz Anastacio Alves
- Laboratory of Cellular Communication, Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de JaneiroRJBrazil
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12
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Synthesis, biological evaluation and molecular modeling studies of novel 1,2,3-triazole-linked menadione-furan derivatives as P2X7 inhibitors. J Bioenerg Biomembr 2022; 54:227-239. [PMID: 36070071 DOI: 10.1007/s10863-022-09947-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 08/29/2022] [Indexed: 10/14/2022]
Abstract
The P2X7 receptor (P2X7R) is an ion channel that promotes the passage of ions through the membrane through brief stimulation once activated by ATP, its endogenous opener. However, prolonged stimulation with ATP, which occurs in pathological processes, opens a nonselective pore in the plasma membrane, allowing the passage of large molecules and leading to cytokine release or even cell death. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Considering the booming of biomass upgrading reactions in recent years and the continued efforts to synthesize biologically active molecules containing the 1,2,3-triazole ring, in the present work, we aimed to investigate whether triazole-linked menadione-furan derivatives could present P2X7R inhibitory activity. The novel compounds were tested for their inhibitory activity on ATP-induced dye uptake in peritoneal macrophages. Some have shown promising results, having displayed IC50 values lower than that of the P2X7R inhibitor BBG. Molecular docking studies also indicated that the active compounds bind to an allosteric site on P2X7R, presenting potential P2X7R inhibition.
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13
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Khoza LJ, Kumar P, Dube A, Demana PH, Choonara YE. Insights into Innovative Therapeutics for Drug-Resistant Tuberculosis: Host-Directed Therapy and Autophagy Inducing Modified Nanoparticles. Int J Pharm 2022; 622:121893. [PMID: 35680110 PMCID: PMC9169426 DOI: 10.1016/j.ijpharm.2022.121893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 10/25/2022]
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Lee CB, Lee KI, Kim YJ, Jang IT, Gurmessa SK, Choi EH, Kaushik NK, Kim HJ. Non-Thermal Plasma Jet-Treated Medium Induces Selective Cytotoxicity against Mycobacterium tuberculosis-Infected Macrophages. Biomedicines 2022; 10:biomedicines10061243. [PMID: 35740265 PMCID: PMC9219627 DOI: 10.3390/biomedicines10061243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/14/2022] [Accepted: 05/24/2022] [Indexed: 11/30/2022] Open
Abstract
Plasma-treated media (PTM) serve as an adjuvant therapy to postoperatively remove residual cancerous lesions. We speculated that PTM could selectively kill cells infected with Mycobacterium tuberculosis (Mtb) and remove postoperative residual tuberculous lesions. We therefore investigated the effects of a medium exposed to a non-thermal plasma jet on the suppression of intracellular Mtb replication, cell death, signaling, and selectivity. We propose that PTM elevates the levels of the detoxifying enzymes, glutathione peroxidase, catalase, and ataxia-telangiectasia mutated serine/threonine kinase and increases intracellular reactive oxygen species production in Mtb-infected cells. The bacterial load was significantly decreased in spleen and lung tissues and single-cell suspensions from mice intraperitoneally injected with PTM compared with saline and untreated medium. Therefore, PTM has the potential as a novel treatment that can eliminate residual Mtb-infected cells after infected tissues are surgically resected.
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Affiliation(s)
- Chae Bok Lee
- Department of Microbiology & Medical Science, College of Medicine, Chungnam National University, Daejeon 301-747, Korea; (C.B.L.); (K.I.L.); (Y.J.K.); (I.T.J.); (S.K.G.)
| | - Kang In Lee
- Department of Microbiology & Medical Science, College of Medicine, Chungnam National University, Daejeon 301-747, Korea; (C.B.L.); (K.I.L.); (Y.J.K.); (I.T.J.); (S.K.G.)
| | - Young Jae Kim
- Department of Microbiology & Medical Science, College of Medicine, Chungnam National University, Daejeon 301-747, Korea; (C.B.L.); (K.I.L.); (Y.J.K.); (I.T.J.); (S.K.G.)
| | - In Taek Jang
- Department of Microbiology & Medical Science, College of Medicine, Chungnam National University, Daejeon 301-747, Korea; (C.B.L.); (K.I.L.); (Y.J.K.); (I.T.J.); (S.K.G.)
| | - Sintayehu Kebede Gurmessa
- Department of Microbiology & Medical Science, College of Medicine, Chungnam National University, Daejeon 301-747, Korea; (C.B.L.); (K.I.L.); (Y.J.K.); (I.T.J.); (S.K.G.)
| | - Eun Ha Choi
- Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, Seoul 01897, Korea; (E.H.C.); (N.K.K.)
| | - Nagendra Kumar Kaushik
- Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, Seoul 01897, Korea; (E.H.C.); (N.K.K.)
| | - Hwa-Jung Kim
- Department of Microbiology & Medical Science, College of Medicine, Chungnam National University, Daejeon 301-747, Korea; (C.B.L.); (K.I.L.); (Y.J.K.); (I.T.J.); (S.K.G.)
- Correspondence: ; Tel.: +82-42-580-8242
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15
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Bernardazzi C, Castelo-Branco MTL, Pêgo B, Ribeiro BE, Rosas SLB, Santana PT, Machado JC, Leal C, Thompson F, Coutinho-Silva R, de Souza HSP. The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome. Int J Mol Sci 2022; 23:4616. [PMID: 35563010 PMCID: PMC9099551 DOI: 10.3390/ijms23094616] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 12/12/2022] Open
Abstract
Background: Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). Methods: CA-CRC was induced in P2X7R+/+ and P2X7R-/- mice with azoxymethane (AOM) combined with dextran sodium sulfate (DSS). In a therapeutic protocol, P2X7R+/+ mice were treated with a P2X7R-selective inhibitor (A740003). Mice were evaluated with follow-up video endoscopy with endoluminal ultrasound biomicroscopy. Colon tissue was analyzed for histological changes, densities of immune cells, expression of transcription factors, cytokines, genes, DNA methylation, and microbiome composition of fecal samples by sequencing for 16S rRNA. Results: The P2X7R+/+ mice displayed more ulcers, tumors, and greater wall thickness, than the P2X7R-/- and the P2X7R+/+ mice treated with A740003. The P2X7R+/+ mice showed increased accumulation of immune cells, production of proinflammatory cytokines, activation of intracellular signaling pathways, and upregulation of NLRP3 and NLRP12 genes, stabilized after the P2X7R-blockade. Microbial changes were observed in the P2X7R-/- and P2X7R+/+-induced mice, partially reversed by the A740003 treatment. Conclusions: Regulatory mechanisms activated downstream of the P2X7R in combination with signals from a dysbiotic microbiota result in the activation of intracellular signaling pathways and the inflammasome, amplifying the inflammatory response and promoting CA-CRC development.
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Affiliation(s)
- Claudio Bernardazzi
- Department of Pediatrics, University of Arizona, Tucson, AZ 85724, USA;
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (M.T.L.C.-B.); (B.P.); (B.E.R.); (S.L.B.R.); (P.T.S.)
| | - Morgana Teixeira Lima Castelo-Branco
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (M.T.L.C.-B.); (B.P.); (B.E.R.); (S.L.B.R.); (P.T.S.)
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil
| | - Beatriz Pêgo
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (M.T.L.C.-B.); (B.P.); (B.E.R.); (S.L.B.R.); (P.T.S.)
| | - Beatriz Elias Ribeiro
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (M.T.L.C.-B.); (B.P.); (B.E.R.); (S.L.B.R.); (P.T.S.)
| | - Siane Lopes Bittencourt Rosas
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (M.T.L.C.-B.); (B.P.); (B.E.R.); (S.L.B.R.); (P.T.S.)
| | - Patrícia Teixeira Santana
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (M.T.L.C.-B.); (B.P.); (B.E.R.); (S.L.B.R.); (P.T.S.)
| | - João Carlos Machado
- Biomedical Engineering Program, COPPE, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil;
| | - Camille Leal
- Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-599, Brazil; (C.L.); (F.T.)
| | - Fabiano Thompson
- Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-599, Brazil; (C.L.); (F.T.)
| | - Robson Coutinho-Silva
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil;
| | - Heitor Siffert Pereira de Souza
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil; (M.T.L.C.-B.); (B.P.); (B.E.R.); (S.L.B.R.); (P.T.S.)
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro 22281-100, Brazil
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16
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Cai X, Yao Y, Teng F, Li Y, Wu L, Yan W, Lin N. The role of P2X7 receptor in infection and metabolism: Based on inflammation and immunity. Int Immunopharmacol 2021; 101:108297. [PMID: 34717202 DOI: 10.1016/j.intimp.2021.108297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/20/2022]
Abstract
The P2X7 receptor (P2X7R) is a ligand-gated receptor belonging to the P2 receptor family. It is distributed in various tissues of the human body and is involved in regulating the physiological functions of tissues and cells to affect the occurrence and development of diseases. Unlike all other P2 receptors, the P2X7 receptor is mainly expressed in immune cells and can be activated not only by extracellular nucleotides but also by non-nucleotide substances which act as positive allosteric modulators. In this review, we comprehensively describe the role of the P2X7 receptor in infection and metabolism based on its role as an important regulator of inflammation and immunity, and briefly introduce the structure and general function of the P2X7 receptor. These provide a clear knowledge framework for the study of the P2X7 receptor in human health. Targeting the P2X7 receptor may be an effective method for the treatment of inflammatory and immune diseases. And its role in microbial infection and metabolism may be the main direction for in-depth research on the P2X7 receptor in the future.
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Affiliation(s)
- Xiaoyu Cai
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yao Yao
- Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou 310006, China
| | - Fei Teng
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yangling Li
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Linwen Wu
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Wei Yan
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China.
| | - Nengming Lin
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China; College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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17
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Gupta A, Sinha KM, Abdin MZ, Puri N, Selvapandiyan A. NDK/NME proteins: a host-pathogen interface perspective towards therapeutics. Curr Genet 2021; 68:15-25. [PMID: 34480234 DOI: 10.1007/s00294-021-01198-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 06/18/2021] [Accepted: 06/19/2021] [Indexed: 12/12/2022]
Abstract
No effective vaccine is available for any parasitic disease. The treatment to those is solely dependent on chemotherapy, which is always threatened due to development of drug resistance in bugs. This warrants identification of new drug targets. Here, we discuss Nucleoside diphosphate kinases (NDKs) of pathogens that alter host's intra and extracellular environment, as novel drug targets to simultaneously tackle multiple pathogens. NDKs having diverse functions, are highly conserved among prokaryotes and eukaryotes (the mammal NDKs are called NMEs [non-metastatic enzymes]). However, NDKs and NMEs have been separately analysed in the past for their structure and functions. The role of NDKs of pathogen in modulation of inflammation, phagocytosis, apoptosis, and ROS generation in host is known. Conversely, its combined contribution in host-pathogen interaction has not been studied yet. Through the sequence and domain analysis, we found that NDKs can be classified in two groups. One group comprised NMEs 1-4 and few NDKs of select essential protozoan parasites and the bacterium Mycobacterium tuberculosis. The other group included NME7 and the other NDKs of those parasites, posing challenges in the development of drugs specifically targeting pathogen NDKs, without affecting NME7. However, common drugs targeting group 2 NDKs of pathogens can be designed, as NME7 of group 2 is expressed only in ciliated host cells. This review thus analyses comparatively for the first time the structures and functions of human NMEs and pathogen NDKs and predicts the possibilities of NDKs as drug targets. In addition, pathogen NDKs have been now provided a nomenclature in alignment with the NMEs of humans.
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Affiliation(s)
- Ankit Gupta
- Department of Molecular Medicine, School of Interdisciplinary Sciences and Technology, Jamia Hamdard, New Delhi, 110062, India
| | - Krishna Murari Sinha
- Amity Institute of Biotechnology, Amity University Haryana, Gurgaon, Haryana, 122413, India
| | - Malik Z Abdin
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Niti Puri
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Angamuthu Selvapandiyan
- Department of Molecular Medicine, School of Interdisciplinary Sciences and Technology, Jamia Hamdard, New Delhi, 110062, India.
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18
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Rasi V, Wood DC, Eickhoff CS, Xia M, Pozzi N, Edwards RL, Walch M, Bovenschen N, Hoft DF. Granzyme A Produced by γ 9δ 2 T Cells Activates ER Stress Responses and ATP Production, and Protects Against Intracellular Mycobacterial Replication Independent of Enzymatic Activity. Front Immunol 2021; 12:712678. [PMID: 34413857 PMCID: PMC8368726 DOI: 10.3389/fimmu.2021.712678] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/12/2021] [Indexed: 01/14/2023] Open
Abstract
Mycobacterium tuberculosis (Mtb), the pathological agent that causes tuberculosis (TB) is the number one infectious killer worldwide with one fourth of the world's population currently infected. Data indicate that γ9δ2 T cells secrete Granzyme A (GzmA) in the extracellular space triggering the infected monocyte to inhibit growth of intracellular mycobacteria. Accordingly, deletion of GZMA from γ9δ2 T cells reverses their inhibitory capacity. Through mechanistic studies, GzmA's action was investigated in monocytes from human PBMCs. The use of recombinant human GzmA expressed in a mammalian system induced inhibition of intracellular mycobacteria to the same degree as previous human native protein findings. Our data indicate that: 1) GzmA is internalized within mycobacteria-infected cells, suggesting that GzmA uptake could prevent infection and 2) that the active site is not required to inhibit intracellular replication. Global proteomic analysis demonstrated that the ER stress response and ATP producing proteins were upregulated after GzmA treatment, and these proteins abundancies were confirmed by examining their expression in an independent set of patient samples. Our data suggest that immunotherapeutic host interventions of these pathways may contribute to better control of the current TB epidemic.
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Affiliation(s)
- Valerio Rasi
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States,Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - David C. Wood
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Christopher S. Eickhoff
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Mei Xia
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Nicola Pozzi
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Rachel L. Edwards
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Michael Walch
- Anatomy Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Niels Bovenschen
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Daniel F. Hoft
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States,Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States,*Correspondence: Daniel F. Hoft,
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Subedi B, Anderson S, Croft TL, Rouchka EC, Zhang M, Hammond-Weinberger DR. Gene alteration in zebrafish exposed to a mixture of substances of abuse. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 278:116777. [PMID: 33689951 PMCID: PMC8053679 DOI: 10.1016/j.envpol.2021.116777] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/23/2021] [Accepted: 02/15/2021] [Indexed: 06/12/2023]
Abstract
A recent surge in the use and abuse of diverse prescribed psychotic and illicit drugs necessitates the surveillance of drug residues in source water and the associated ecological impacts of chronic exposure to the aquatic organism. Thirty-six psychotic and illicit drug residues were determined in discharged wastewater from two centralized municipal wastewater treatment facilities and two wastewater receiving creeks for seven consecutive days in Kentucky. Zebrafish (Danio rerio) larvae were exposed to the environmental relevant mixtures of all drug residues, all illicit drugs, and all prescribed psychotic drugs. The extracted RNA from fish homogenates was sequenced, and differentially expressed sequences were analyzed for known or predicted nervous system expression, and screened annotated protein-coding genes to the true environmental cocktail mixture. Illicit stimulant (cocaine and one metabolite), opioids (methadone, methadone metabolite, and oxycodone), hallucinogen (MDA), benzodiazepine (oxazepam and temazepam), carbamazepine, and all target selective serotonin reuptake inhibitors including sertraline, fluoxetine, venlafaxine, and citalopram were quantified in 100% of collected samples from both creeks. The high dose cocktail mixture exposure group revealed the largest group of differentially expressed genes: 100 upregulated and 77 downregulated (p ≤ 0.05; q ≤ 0.05). The top 20 differentially expressed sequences in each exposure group comprise 82 unique transcripts corresponding to 74% annotated genes, 7% non-coding sequences, and 19% uncharacterized sequences. Among 61 differentially expressed sequences that corresponded to annotated protein-coding genes, 23 (38%) genes or their homologs are known to be expressed in the nervous system of fish or other organisms. Several of the differentially expressed sequences are associated primarily with the immune system, including several major histocompatibility complex class I and interferon-induced proteins. Interleukin-1 beta (downregulated in this study) abnormalities are considered a risk factor for psychosis. This is the first study to assess the contributions of multiple classes of psychotic and illicit drugs in combination with developmental gene expression.
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Affiliation(s)
- B Subedi
- Department of Chemistry, Murray State University, Murray, KY, United States.
| | - S Anderson
- Department of Biology, Murray State University, Murray, KY, United States
| | - T L Croft
- Department of Chemistry, Murray State University, Murray, KY, United States
| | - E C Rouchka
- Department of Computer Science and Engineering, University of Louisville, Louisville, KY, United States; KBRIN Bioinformatics Core, University of Louisville, Louisville, KY, United States
| | - M Zhang
- Genomics Facility University of Louisville, Louisville, KY, United States
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Lovászi M, Branco Haas C, Antonioli L, Pacher P, Haskó G. The role of P2Y receptors in regulating immunity and metabolism. Biochem Pharmacol 2021; 187:114419. [PMID: 33460626 DOI: 10.1016/j.bcp.2021.114419] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/07/2021] [Accepted: 01/11/2021] [Indexed: 02/07/2023]
Abstract
P2Y receptors are G protein-coupled receptors whose physiological agonists are the nucleotides ATP, ADP, UTP, UDP and UDP-glucose. Eight P2Y receptors have been cloned in humans: P2Y1R, P2Y2R, P2Y4R, P2Y6R, P2Y11R, P2Y12R, P2Y13R and P2Y14R. P2Y receptors are expressed in lymphoid tissues such as thymus, spleen and bone marrow where they are expressed on lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, mast cells, and platelets. P2Y receptors regulate many aspects of immune cell function, including phagocytosis and killing of pathogens, antigen presentation, chemotaxis, degranulation, cytokine production, and lymphocyte activation. Consequently, P2Y receptors shape the course of a wide range of infectious, autoimmune, and inflammatory diseases. P2Y12R ligands have already found their way into the therapeutic arena, and we envision additional ligands as future drugs for the treatment of diseases caused by or associated with immune dysregulation.
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Affiliation(s)
- Marianna Lovászi
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | | | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Pál Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA.
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21
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Maphasa RE, Meyer M, Dube A. The Macrophage Response to Mycobacterium tuberculosis and Opportunities for Autophagy Inducing Nanomedicines for Tuberculosis Therapy. Front Cell Infect Microbiol 2021; 10:618414. [PMID: 33628745 PMCID: PMC7897680 DOI: 10.3389/fcimb.2020.618414] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/18/2020] [Indexed: 12/23/2022] Open
Abstract
The major causative agent of tuberculosis (TB), i.e., Mycobacterium tuberculosis (Mtb), has developed mechanisms to evade host defense responses and persist within host cells for prolonged periods of time. Mtb is also increasingly resistant to existing anti-TB drugs. There is therefore an urgent need to develop new therapeutics for TB and host directed therapies (HDTs) hold potential as effective therapeutics for TB. There is growing interest in the induction of autophagy in Mtb host cells using autophagy inducing compounds (AICs). Nanoparticles (NPs) can enhance the effect of AICs, thus improving stability, enabling cell targeting and providing opportunities for multimodal therapy. In this review, we focus on the macrophage responses to Mtb infection, in particular, the mechanistic aspects of autophagy and the evasion of autophagy by intracellular Mtb. Due to the overlap between the onset of autophagy and apoptosis; we also focus on the relationship between apoptosis and autophagy. We will also review known AICs in the context of Mtb infection. Finally, we discuss the applications of NPs in inducing autophagy with the intention of sharing insights to encourage further research and development of nanomedicine HDTs for TB therapy.
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Affiliation(s)
- Retsepile E Maphasa
- Infectious Disease Nanomedicine Research Group, School of Pharmacy, University of the Western Cape, Cape Town, South Africa
| | - Mervin Meyer
- DST/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, University of the Western Cape, Cape Town, South Africa
| | - Admire Dube
- Infectious Disease Nanomedicine Research Group, School of Pharmacy, University of the Western Cape, Cape Town, South Africa
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22
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Vargas-Martínez EM, Gómez-Coronado KS, Espinosa-Luna R, Valdez-Morales EE, Barrios-García T, Barajas-Espinosa A, Ochoa-Cortes F, Montaño LM, Barajas-López C, Guerrero-Alba R. Functional expression of P2X1, P2X4 and P2X7 purinergic receptors in human monocyte-derived macrophages. Eur J Pharmacol 2020; 888:173460. [PMID: 32805257 DOI: 10.1016/j.ejphar.2020.173460] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/20/2020] [Accepted: 07/31/2020] [Indexed: 12/27/2022]
Abstract
This study sought to examine the co-expression of the following purinergic receptor subunits: P2X1, P2X1del, P2X4, and P2X7 and characterize the P2X response in human monocyte-derived macrophages (MDMs). Single-cell RT-PCR shows the presence of P2X1, P2X1del, P2X4, and P2X7 mRNA in 40%, 5%, 20%, and 90% of human MDMs, respectively. Of the studied human MDMs, 25% co-expressed P2X1 and P2X7 mRNA; 5% co-expressed P2X4 and P2X7; and 15% co-expressed P2X1, P2X4, and P2X7 mRNA. In whole-cell patch clamp recordings of human MDMs, rapid application of ATP (0.01 mM) evoked fast current activation and two different desensitization kinetics: 1. a rapid desensitizing current antagonized by PPADS (1 μM), reminiscent of the P2X1 receptor's current; 2. a slow desensitizing current, insensitive to PPADS but potentiated by ivermectin (3 μM), similar to the P2X4 receptor's current. Application of 5 mM ATP induced three current modalities: 1. slow current activation with no desensitization, similar to the P2X7 receptor current, present in 69% of human macrophages and antagonized by A-804598 (0.1 μM); 2. fast current activation and fast desensitization, present in 15% of human MDMs; 3. fast activation current followed by biphasic desensitization, observed in 15% of human MDMs. Both rapid and biphasic desensitization kinetics resemble those observed for the recombinant human P2X1 receptor expressed in oocytes. These data demonstrate, for the first time, the co-expression of P2X1, P2X4, and P2X7 transcripts and confirm the presence of functional P2X1, P2X4, and P2X7 receptors in human macrophages.
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Affiliation(s)
- Eydie M Vargas-Martínez
- División de Biología Molecular, Instituto Potosino Investigación Científica y Tecnológica, San Luis Potosí, SLP, México
| | - Karen S Gómez-Coronado
- División de Biología Molecular, Instituto Potosino Investigación Científica y Tecnológica, San Luis Potosí, SLP, México
| | - Rosa Espinosa-Luna
- División de Biología Molecular, Instituto Potosino Investigación Científica y Tecnológica, San Luis Potosí, SLP, México
| | - Eduardo E Valdez-Morales
- Catedras CONACYT, Departamento de Medicina, Centro de Ciencias de la Salud, Universidad Autónoma de Aguascalientes, Aguascalientes, México
| | - Tonatiuh Barrios-García
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, México
| | - Alma Barajas-Espinosa
- Licenciatura en Enfermería, Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Huejutla de Reyes, Hidalgo, México
| | - Fernando Ochoa-Cortes
- Licenciatura en Enfermería, Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Huejutla de Reyes, Hidalgo, México
| | - Luis M Montaño
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, México
| | - Carlos Barajas-López
- División de Biología Molecular, Instituto Potosino Investigación Científica y Tecnológica, San Luis Potosí, SLP, México
| | - Raquel Guerrero-Alba
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, México.
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23
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Xu S, Lin Y, Zhu X, Liu D, Tong M, Liu L, Yang T, Lin L. Autophagy promotes phagocytosis and clearance of
Treponema pallidum
via the NLRP3 inflammasome in macrophages. J Eur Acad Dermatol Venereol 2020; 34:2111-2119. [PMID: 32294266 DOI: 10.1111/jdv.16463] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/10/2020] [Indexed: 12/17/2022]
Affiliation(s)
- S.‐L. Xu
- Center of Clinical Laboratory Zhongshan Hospital School of Medicine Xiamen University Xiamen China
- Institute of Infectious Disease School of Medicine Xiamen University Xiamen China
| | - Y. Lin
- Center of Clinical Laboratory Zhongshan Hospital School of Medicine Xiamen University Xiamen China
- Institute of Infectious Disease School of Medicine Xiamen University Xiamen China
| | - X.‐Z. Zhu
- Center of Clinical Laboratory Zhongshan Hospital School of Medicine Xiamen University Xiamen China
- Institute of Infectious Disease School of Medicine Xiamen University Xiamen China
| | - D. Liu
- Center of Clinical Laboratory Zhongshan Hospital School of Medicine Xiamen University Xiamen China
- Institute of Infectious Disease School of Medicine Xiamen University Xiamen China
| | - M.‐L. Tong
- Center of Clinical Laboratory Zhongshan Hospital School of Medicine Xiamen University Xiamen China
- Institute of Infectious Disease School of Medicine Xiamen University Xiamen China
| | - L.‐L. Liu
- Center of Clinical Laboratory Zhongshan Hospital School of Medicine Xiamen University Xiamen China
- Institute of Infectious Disease School of Medicine Xiamen University Xiamen China
| | - T.‐C. Yang
- Center of Clinical Laboratory Zhongshan Hospital School of Medicine Xiamen University Xiamen China
- Institute of Infectious Disease School of Medicine Xiamen University Xiamen China
| | - L.‐R. Lin
- Center of Clinical Laboratory Zhongshan Hospital School of Medicine Xiamen University Xiamen China
- Institute of Infectious Disease School of Medicine Xiamen University Xiamen China
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24
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Duan H, Ni S, Yang S, Zhou Y, Zhang Y, Zhang S. Conservation of eATP perception throughout multicellular animal evolution: Identification and functional characterization of coral and amphioxus P2X7-like receptors and flounder P2X7 receptor. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 106:103641. [PMID: 32045589 DOI: 10.1016/j.dci.2020.103641] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 02/07/2020] [Accepted: 02/07/2020] [Indexed: 06/10/2023]
Abstract
Perception of extracellular ATP (eATP), a common endogenous damage-associated molecular pattern, is through its receptor P2X7R. If eATP/P2X7R signaling is conserved throughout animal evolution is unknown. Moreover, little information is currently available regarding P2X7R in invertebrates. Here we demonstrated that the coral P2X7-like receptor, AdP2X7RL, the amphioxus P2X7-like receptor, BjP2X7RL and the flounder P2X7 receptor, PoP2X7R, shared common features characteristic of mammalian P2X7R, and their 3D structures displayed high resemblance to that of human P2X7R. Expression of Adp2x7rl, Bjp2x7rl and Pop2x7r was all subjected to the regulation by LPS and ATP. We also showed that AdP2X7RL, BjP2X7RL and PoP2X7R were distributed on the plasma membrane in AdP2X7RL-, BjP2X7RL- and PoP2X7R-expressing HEK cells, and had strong affinity to eATP. Importantly, the binding of AdP2X7RL, BjP2X7RL and PoP2X7R to eATP all induced similar downstream responses, including induction of cytokines (IL-1β, IL-6, IL-8 and CCL-2), enhancement of phagocytosis and activation of AKT/ERK-associated signaling pathway observed for mammalian P2X7R. Collectively, our results indicate for the first time that both coral and amphioxus P2X7RL as well as flounder P2X7R can interact with eATP, and induce events that trigger mammalian mechanisms, suggesting the high conservation of eATP perception throughout multicellular animal evolution.
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Affiliation(s)
- Huimin Duan
- Institute of Evolution and Marine Biodiversity, Department of Marine Biology, Ocean University of China, Qingdao, 266003, China
| | - Shousheng Ni
- Institute of Evolution and Marine Biodiversity, Department of Marine Biology, Ocean University of China, Qingdao, 266003, China
| | - Shuaiqi Yang
- Institute of Evolution and Marine Biodiversity, Department of Marine Biology, Ocean University of China, Qingdao, 266003, China
| | - Yang Zhou
- Institute of Evolution and Marine Biodiversity, Department of Marine Biology, Ocean University of China, Qingdao, 266003, China
| | - Yu Zhang
- Institute of Evolution and Marine Biodiversity, Department of Marine Biology, Ocean University of China, Qingdao, 266003, China.
| | - Shicui Zhang
- Institute of Evolution and Marine Biodiversity, Department of Marine Biology, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266003, China.
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25
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Basu M, Gupta P, Dutta A, Jana K, Ukil A. Increased host ATP efflux and its conversion to extracellular adenosine is crucial for establishing Leishmania infection. J Cell Sci 2020; 133:jcs239939. [PMID: 32079656 DOI: 10.1242/jcs.239939] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/07/2020] [Indexed: 12/19/2022] Open
Abstract
Intracellular survival of Leishmania donovani demands rapid production of host ATP for its sustenance. However, a gradual decrease in intracellular ATP in spite of increased glycolysis suggests ATP efflux during infection. Accordingly, upon infection, we show here that ATP is exported and the major exporter was pannexin-1, leading to raised extracellular ATP levels. Extracellular ATP shows a gradual decrease after the initial increase, and analysis of cell surface ATP-degrading enzymes revealed induction of the ectonucleotidases CD39 and CD73. Ectonucleotidase-mediated ATP degradation leads to increased extracellular adenosine (eADO), and inhibition of CD39 and CD73 in infected cells decreased adenosine concentration and parasite survival, documenting the importance of adenosine in infection. Inhibiting adenosine uptake by cells did not affect parasite survival, suggesting that eADO exerts its effect through receptor-mediated signalling. We also show that Leishmania induces the expression of adenosine receptors A2AR and A2BR, both of which are important for anti-inflammatory responses. Treating infected BALB/c mice with CD39 and CD73 inhibitors resulted in decreased parasite burden and increased host-favourable cytokine production. Collectively, these observations indicate that infection-induced ATP is exported, and after conversion into adenosine, propagates infection via receptor-mediated signalling.
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Affiliation(s)
- Moumita Basu
- Department of Biochemistry, University of Calcutta, Kolkata 700019, West Bengal, India
| | - Purnima Gupta
- Infections and Cancer Biology Group, International Agency for Research on Cancer, 69372, Lyon Cedex 08, France
| | - Ananya Dutta
- Division of Molecular Medicine, Bose Institute, P1/12 Calcutta Improvement Trust Scheme, VIIM, Kolkata, 700054, West Bengal, India
| | - Kuladip Jana
- Division of Molecular Medicine, Bose Institute, P1/12 Calcutta Improvement Trust Scheme, VIIM, Kolkata, 700054, West Bengal, India
| | - Anindita Ukil
- Department of Biochemistry, University of Calcutta, Kolkata 700019, West Bengal, India
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26
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Ruhl CR, Pasko BL, Khan HS, Kindt LM, Stamm CE, Franco LH, Hsia CC, Zhou M, Davis CR, Qin T, Gautron L, Burton MD, Mejia GL, Naik DK, Dussor G, Price TJ, Shiloh MU. Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough. Cell 2020; 181:293-305.e11. [PMID: 32142653 PMCID: PMC7102531 DOI: 10.1016/j.cell.2020.02.026] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/13/2020] [Accepted: 02/10/2020] [Indexed: 12/11/2022]
Abstract
Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.
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Affiliation(s)
- Cody R Ruhl
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Breanna L Pasko
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Haaris S Khan
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lexy M Kindt
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Chelsea E Stamm
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Luis H Franco
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Connie C Hsia
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Min Zhou
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Colton R Davis
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tian Qin
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Laurent Gautron
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Michael D Burton
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Galo L Mejia
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Dhananjay K Naik
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Gregory Dussor
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Theodore J Price
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Michael U Shiloh
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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27
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Rump A, Smolander OP, Rüütel Boudinot S, Kanellopoulos JM, Boudinot P. Evolutionary Origin of the P2X7 C-ter Region: Capture of an Ancient Ballast Domain by a P2X4-Like Gene in Ancient Jawed Vertebrates. Front Immunol 2020; 11:113. [PMID: 32117264 PMCID: PMC7016195 DOI: 10.3389/fimmu.2020.00113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Accepted: 01/16/2020] [Indexed: 01/31/2023] Open
Abstract
P2X purinergic receptors are extracellular ATP-gated ion channel receptors present on the cell plasma membrane. P2X receptors have been found in Metazoa, fungi, amoebas, and in plants. In mammals, P2X7 is expressed by a large number of cell types and is involved in inflammation and immunity. Remarkably, P2X7 does not desensitize as other P2X do, a feature linked to a “C-cysteine anchor” intra-cytoplasmic motif encoded by exon 11. Another specific feature of P2X7 is its C-terminal cytoplasmic ballast domain (exon 13) which contains a zinc (Zn) coordinating cysteine motif and a GDP-binding region. To determine the origin of P2X7, we analyzed and compared sequences and protein motifs of the C-terminal intra-cytoplasmic region across all main groups of Metazoa. We identified proteins with typical ballast domains, sharing a remarkably conserved Zn-coordinating cysteine motif. Apart from vertebrates, these ballast domains were not associated with a typical P2X architecture. These results strongly suggest that P2X7 resulted from the fusion of a P2X gene, highly similar to P2X4, with an exon encoding a ballast domain. Our work brings new evidence on the origin of the P2X7 purinergic receptor and identifies the Zn-coordinating cysteine domain as the fundamental feature of the ancient ballast fold.
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Affiliation(s)
- Airi Rump
- Immunology Unit, Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Olli Pekka Smolander
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Sirje Rüütel Boudinot
- Immunology Unit, Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Jean M Kanellopoulos
- Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, Gif-sur-Yvette, France
| | - Pierre Boudinot
- Virologie et Immunologie Moléculaires, INRAE, Université Paris Saclay, Jouy en Josas, France
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28
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Molecular Mechanisms of Calcium Signaling During Phagocytosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1246:103-128. [PMID: 32399828 DOI: 10.1007/978-3-030-40406-2_7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Calcium (Ca2+) is a ubiquitous second messenger involved in the regulation of numerous cellular functions including vesicular trafficking, cytoskeletal rearrangements and gene transcription. Both global as well as localized Ca2+ signals occur during phagocytosis, although their functional impact on the phagocytic process has been debated. After nearly 40 years of research, a consensus may now be reached that although not strictly required, Ca2+ signals render phagocytic ingestion and phagosome maturation more efficient, and their manipulation make an attractive avenue for therapeutic interventions. In the last decade many efforts have been made to identify the channels and regulators involved in generating and shaping phagocytic Ca2+ signals. While molecules involved in store-operated calcium entry (SOCE) of the STIM and ORAI family have taken center stage, members of the canonical, melastatin, mucolipin and vanilloid transient receptor potential (TRP), as well as purinergic P2X receptor families are now recognized to play significant roles. In this chapter, we review the recent literature on research that has linked specific Ca2+-permeable channels and regulators to phagocytic function. We highlight the fact that lipid mediators are emerging as important regulators of channel gating and that phagosomal ionic homeostasis and Ca2+ release also play essential parts. We predict that improved methodologies for measuring these factors will be critical for future advances in dissecting the intricate biology of this fascinating immune process.
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29
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Khan SR, Manialawy Y, Siraki AG. Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action. Br J Pharmacol 2019; 176:4599-4608. [PMID: 31517993 DOI: 10.1111/bph.14867] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 08/16/2019] [Accepted: 09/04/2019] [Indexed: 12/19/2022] Open
Abstract
The known mode of action of isoniazid (INH) is to inhibit bacterial cell wall synthesis following activation by the bacterial catalase-peroxidase enzyme KatG in Mycobacterium tuberculosis (Mtb). This simplistic model fails to explain (a) how isoniazid penetrates waxy granulomas with its very low lipophilicity, (b) how isoniazid kills latent Mtb lacking a typical cell wall, and (c) why isoniazid treatment time is remarkably long in contrast to most other antibiotics. To address these questions, a novel comprehensive mode of action of isoniazid has been proposed here. Briefly, isoniazid eradicates latent tuberculosis (TB) by prompting slow differentiation of pro-inflammatory monocytes and providing protection against reactive species-induced "self-necrosis" of phagocytes. In the case of active TB, different immune cells form INH-NAD+ adducts to inhibit Mtb's cell wall biosynthesis. This additionally suggests that the antibacterial properties of INH do not rely on KatG of Mtb. As such, isoniazid-resistant TB needs to be re-evaluated.
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Affiliation(s)
- Saifur R Khan
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.,Advanced Diagnostics, Metabolism, Toronto General Research Institute, Ontario, Canada
| | - Yousef Manialawy
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.,Advanced Diagnostics, Metabolism, Toronto General Research Institute, Ontario, Canada
| | - Arno G Siraki
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada
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30
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Abstract
Inflammatory bowel disease is a chronic nonspecific inflammatory disease of the intestine. Its pathogenesis is not yet fully understood. It may be related to heredity, environmental triggers, infection, immune dysfunction and other factors. Purinergic receptor (P2X7R) ligand-gated ion channel is closely related to inflammation and widely expressed in intestinal cells. Previous studies have shown that ATP/P2X7R signal is involved in the pathogenesis of intestinal inflammation, but its specific mechanism needs further study. This article reviews the research progress of P2X7 receptor in inflammatory bowel disease.
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Affiliation(s)
- Yajun Liu
- a Department of Gastroenterology , Xiangya Hospital, Central South University , Changsha , China
| | - Xiaowei Liu
- a Department of Gastroenterology , Xiangya Hospital, Central South University , Changsha , China
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31
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Mellouk A, Bobé P. CD8 +, but not CD4 + effector/memory T cells, express the CD44 highCD45RB high phenotype with aging, which displays reduced expression levels of P2X 7 receptor and ATP-induced cellular responses. FASEB J 2018; 33:3225-3236. [PMID: 30383448 DOI: 10.1096/fj.201800867r] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Previously we reported that the sensitivity of CD4+ T cells to ATP does not depend on P2X7 receptor (P2X7R) expression levels but on their activation and differentiation stages. Therefore, here we have investigated a potential relationship between the sensitivity of CD8+ T cells to ATP and their stages of differentiation. Thus, the CD8+ subpopulation exhibits a drastically reduced sensitivity to ATP with aging, which parallels the strong increase of an effector/memory CD8+ subset expressing high levels of CD44 cell adhesion molecule and CD45RB transmembrane phosphatase (CD44hiCD45RBhi). Using l-selectin/CD62L, CC-chemokine receptor 7, and CD127/IL-7 receptor-α markers, we showed that effector/memory CD8+ T cells belong to a central or effector memory subset. In contrast, the CD44hiCD45RBhi effector/memory subset is absent or poorly expressed in the CD4+ T subpopulation regardless of age. While ATP treatment can trigger channel and pore formation, CD62L shedding, phosphatidylserine exposure, and cell death in the CD44loCD45RBhi-naive CD8+ subset, it is unable to induce these cellular activities in the CD44hiCD45RBhi effector/memory CD8+ subset. Importantly, both CD44loCD45RBhi-naive and CD44hiCD45RBhi effector/memory subsets express similar low levels of P2X7R, demonstrating that the sensitivity of CD8+ T cells to ATP depends on the stage of differentiation instead of P2X7R expression levels.-Mellouk, A., Bobé, P. CD8+, but not CD4+ effector/memory T cells, express the CD44highCD45RBhigh phenotype with aging, which displays reduced expression levels of P2X7 receptor and ATP-induced cellular responses.
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Affiliation(s)
- Amine Mellouk
- INSERM, Université Paris-Sud, Université Paris-Saclay, Unité Mixte de Recherche (UMR) 1174, Orsay, France
| | - Pierre Bobé
- INSERM, Université Paris-Sud, Université Paris-Saclay, Unité Mixte de Recherche (UMR) 1174, Orsay, France
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32
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BoseDasgupta S, Pieters J. Macrophage-microbe interaction: lessons learned from the pathogen Mycobacterium tuberculosis. Semin Immunopathol 2018; 40:577-591. [PMID: 30306257 DOI: 10.1007/s00281-018-0710-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 09/17/2018] [Indexed: 02/07/2023]
Abstract
Macrophages, being the cornerstone of the immune system, have adapted the ancient nutrient acquisition mechanism of phagocytosis to engulf various infectious organisms thereby helping to orchestrate an appropriate host response. Phagocytosis refers to the process of internalization and degradation of particulate material, damaged and senescent cells and microorganisms by specialized cells, after which the vesicle containing the ingested particle, the phagosome, matures into acidic phagolysosomes upon fusion with hydrolytic enzyme-containing lysosomes. The destructive power of the macrophage is further exacerbated through the induction of macrophage activation upon a variety of inflammatory stimuli. Despite being the end-point for many phagocytosed microbes, the macrophage can also serve as an intracellular survival niche for a number of intracellular microorganisms. One microbe that is particularly successful at surviving within macrophages is the pathogen Mycobacterium tuberculosis, which can efficiently manipulate the macrophage at several levels, including modulation of the phagocytic pathway as well as interfering with a number of immune activation pathways that normally would lead to eradication of the internalized bacilli. M. tuberculosis excels at circumventing destruction within macrophages, thus establishing itself successfully for prolonged times within the macrophage. In this contribution, we describe a number of general features of macrophages in the context of their function to clear an infection, and highlight the strategies employed by M. tuberculosis to counter macrophage attack. Interestingly, research on the evasion tactics employed by M. tuberculosis within macrophages not only helps to design strategies to curb tuberculosis, but also allows a better understanding of host cell biology.
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Affiliation(s)
- Somdeb BoseDasgupta
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India.
| | - Jean Pieters
- Department of Biochemistry, Biozentrum, University of Basel, 50-70 Klingelbergstrasse, 4056, Basel, Switzerland.
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Pacheco PAF, Dantas LP, Ferreira LGB, Faria RX. Purinergic receptors and neglected tropical diseases: why ignore purinergic signaling in the search for new molecular targets? J Bioenerg Biomembr 2018; 50:307-313. [PMID: 29882206 DOI: 10.1007/s10863-018-9761-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 05/07/2018] [Indexed: 12/20/2022]
Abstract
Purinergic receptors are widespread in the human organism and are involved in several physiological functions like neurotransmission, nociception, platelet aggregation, etc. In the immune system, they may regulate the expression and release of pro-inflammatory factors as well as the activation and death of several cell types. It is already described the participation of some purinergic receptors in the inflammation and pathological processes, such as a few neglected tropical diseases (NTDs) which affect more than 1 billion people in the world. Although the high social influence those diseases represent endemic countries, most of them do not have an efficient, safe or affordable drug treatment. In that way, this review aims to discuss the current literature involving purinergic receptor and immune response to NTDs pathogens, which may contribute in the search for new therapeutic possibilities.
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Affiliation(s)
- P A F Pacheco
- Department of Chemistry, Chemistry Institute, Fluminense Federal University, Niterói, Brazil
| | - L P Dantas
- Laboratory of Molecular Virology, Biology Institute, Fluminense Federal University, Niterói, Brazil
| | - L G B Ferreira
- Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
| | - Robson Xavier Faria
- Laboratory of Toxoplasmosis and other Protozoans, FIOCRUZ, Oswaldo Cruz Institute, Rio de Janeiro, Brazil. .,Fundação Oswaldo Cruz, Laboratório de Toxoplasmose e outras Protozooses, Instituto Oswaldo Cruz, Avenida Brasil 4365, sala 32; Manguinhos, Rio de Janeiro, RJ, CEP 21045-900, Brazil.
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34
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Csóka B, Németh ZH, Szabó I, Davies DL, Varga ZV, Pálóczi J, Falzoni S, Di Virgilio F, Muramatsu R, Yamashita T, Pacher P, Haskó G. Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. JCI Insight 2018; 3:e99431. [PMID: 29875325 PMCID: PMC5997389 DOI: 10.1172/jci.insight.99431] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 05/01/2018] [Indexed: 01/08/2023] Open
Abstract
The macrophage is a major phagocytic cell type, and its impaired function is a primary cause of immune paralysis, organ injury, and death in sepsis. An incomplete understanding of the endogenous molecules that regulate macrophage bactericidal activity is a major barrier for developing effective therapies for sepsis. Using an in vitro killing assay, we report here that the endogenous purine ATP augments the killing of sepsis-causing bacteria by macrophages through P2X4 receptors (P2X4Rs). Using newly developed transgenic mice expressing a bioluminescent ATP probe on the cell surface, we found that extracellular ATP levels increase during sepsis, indicating that ATP may contribute to bacterial killing in vivo. Studies with P2X4R-deficient mice subjected to sepsis confirm the role of extracellular ATP acting on P2X4Rs in killing bacteria and protecting against organ injury and death. Results with adoptive transfer of macrophages, myeloid-specific P2X4R-deficient mice, and P2rx4 tdTomato reporter mice indicate that macrophages are essential for the antibacterial, antiinflammatory, and organ protective effects of P2X4Rs in sepsis. Pharmacological targeting of P2X4Rs with the allosteric activator ivermectin protects against bacterial dissemination and mortality in sepsis. We propose that P2X4Rs represent a promising target for drug development to control bacterial growth in sepsis and other infections.
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Affiliation(s)
- Balázs Csóka
- Department of Anesthesiology, Columbia University, New York, New York, USA
| | - Zoltán H. Németh
- Department of Anesthesiology, Columbia University, New York, New York, USA
- Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, USA
- Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA
| | - Ildikó Szabó
- Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
| | - Daryl L. Davies
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, USC, Los Angeles, California, USA
| | - Zoltán V. Varga
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
| | - János Pálóczi
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
| | - Simonetta Falzoni
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Rieko Muramatsu
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Toshihide Yamashita
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Pál Pacher
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, New York, USA
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Safya H, Mellouk A, Legrand J, Le Gall SM, Benbijja M, Kanellopoulos-Langevin C, Kanellopoulos JM, Bobé P. Variations in Cellular Responses of Mouse T Cells to Adenosine-5'-Triphosphate Stimulation Do Not Depend on P2X7 Receptor Expression Levels but on Their Activation and Differentiation Stage. Front Immunol 2018. [PMID: 29535730 PMCID: PMC5835135 DOI: 10.3389/fimmu.2018.00360] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5′-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RBlow Tconvs, but not CD45RBhigh Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RBlow Tconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression. P2X7R expression significantly increases on Tconvs during differentiation from naive CD45RBhighCD44low to effector/memory CD45RBlowCD44high stage. Maximum levels of upregulation are reached on recently activated CD69+ naive and memory Tconvs. Ectonucleotidases CD39 and CD73 expression levels increase in parallel with those of P2X7R. Recently activated CD69+ CD45RBhighCD44low Tconvs, although expressing high levels of P2X7R, fail to cleave homing receptor CD62L after ATP treatment, but efficiently form pores and externalize phosphatidylserine (PS). In contrast, naive CD45RBhighCD44low Tconvs cleave CD62L with high efficiency although they express a lower level of P2X7, thus suggesting that P2X7R levels are not a limiting factor for signaling ATP-induced cellular responses. Contrary to common assumption, P2X7R-mediated cellular activities in mouse Tconvs are not triggered in an all-or-none manner, but depend on their stage of activation/differentiation. Compared to CD45RBlow Tconvs, CD45RBlowFoxp3+ Tregs show significantly higher levels of P2X7R membrane expression and of sensitivity to ATP as evidenced by their high levels of CD62L shedding, pore formation and PS externalization observed after ATP treatment. In summary, the different abilities of ATP-treated Tconvs to form pore or cleave CD62L depending on their activation and differentiation state suggests that P2X7R signaling varies according to the physiological role of T convs during antigen activation in secondary lymphoid organs or trafficking to inflammatory sites.
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Affiliation(s)
- Hanaa Safya
- UMR1174, INSERM, Université Paris-Sud, Orsay, France
| | - Amine Mellouk
- UMR1174, INSERM, Université Paris-Sud, Orsay, France
| | - Julie Legrand
- Institut André Lwoff, CNRS, Université Paris-Sud, Villejuif, France
| | - Sylvain M Le Gall
- Institut André Lwoff, CNRS, Université Paris-Sud, Villejuif, France.,UMR 970, INSERM, Université Paris Descartes, Paris, France
| | - Mohcine Benbijja
- Institut André Lwoff, CNRS, Université Paris-Sud, Villejuif, France.,UMR 1012, INSERM, Université Paris-Sud, Le Kremlin Bicêtre, France
| | | | | | - Pierre Bobé
- UMR1174, INSERM, Université Paris-Sud, Orsay, France.,Institut André Lwoff, CNRS, Université Paris-Sud, Villejuif, France
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36
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Pahari S, Kaur G, Negi S, Aqdas M, Das DK, Bashir H, Singh S, Nagare M, Khan J, Agrewala JN. Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis. Front Immunol 2018; 9:193. [PMID: 29479353 PMCID: PMC5811511 DOI: 10.3389/fimmu.2018.00193] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 01/23/2018] [Indexed: 12/12/2022] Open
Abstract
The mononuclear phagocyte system (MPS) constitutes dendritic cells, monocytes, and macrophages. This system contributes to various functions that are essential for maintaining homeostasis, activation of innate immunity, and bridging it with the adaptive immunity. Consequently, MPS is highly important in bolstering immunity against the pathogens. However, MPS is the frontline cells in destroying Mycobacterium tuberculosis (Mtb), yet the bacterium prefers to reside in the hostile environment of macrophages. Therefore, it may be very interesting to study the struggle between Mtb and MPS to understand the outcome of the disease. In an event when MPS predominates Mtb, the host remains protected. By contrast, the situation becomes devastating when the pathogen tames and tunes the host MPS, which ultimately culminates into tuberculosis (TB). Hence, it becomes extremely crucial to reinvigorate MPS functionality to overwhelm Mtb and eliminate it. In this article, we discuss the strategies to bolster the function of MPS by exploiting the molecules associated with the innate immunity and highlight the mechanisms involved to overcome the Mtb-induced suppression of host immunity. In future, such approaches may provide an insight to develop immunotherapeutics to treat TB.
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Affiliation(s)
- Susanta Pahari
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Gurpreet Kaur
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Shikha Negi
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Mohammad Aqdas
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Deepjyoti K Das
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Hilal Bashir
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Sanpreet Singh
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Mukta Nagare
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Junaid Khan
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Javed N Agrewala
- Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India
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37
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Dou L, Chen YF, Cowan PJ, Chen XP. Extracellular ATP signaling and clinical relevance. Clin Immunol 2017; 188:67-73. [PMID: 29274390 DOI: 10.1016/j.clim.2017.12.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/12/2017] [Accepted: 12/20/2017] [Indexed: 12/20/2022]
Abstract
Since purinergic signaling was discovered in the early 1970s, it has been shown that extracellular nucleotides, and their derivative nucleosides, are released in a regulated or unregulated manner by cells in various challenging settings and then bind defined purinergic receptors to activate intricate signaling networks. Extracellular ATP plays a role based on different P2 receptor subtypes expressed on specific cell types. Sequential hydrolysis of extracellular ATP catalyzed by ectonucleotidases (e.g. CD39, CD73) is the main pathway for the generation of adenosine, which in turn activates P1 receptors. Many studies have demonstrated that extracellular ATP signaling functions as an important dynamic regulatory pathway to coordinate appropriate immune responses in various pathological processes, including intracellular infection, host-tumor interaction, pro-inflammation vascular injury, and transplant immunity. ATP receptors and CD39 also participate in related clinical settings. Here, we review the latest research in to the development of promising clinical treatment strategies.
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Affiliation(s)
- Lei Dou
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi-Fa Chen
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Peter J Cowan
- Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia.
| | - Xiao-Ping Chen
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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38
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Butler RE, Krishnan N, Garcia-Jimenez W, Francis R, Martyn A, Mendum T, Felemban S, Locker N, Salguero FJ, Robertson B, Stewart GR. Susceptibility of Mycobacterium tuberculosis-infected host cells to phospho-MLKL driven necroptosis is dependent on cell type and presence of TNFα. Virulence 2017; 8:1820-1832. [PMID: 28892415 PMCID: PMC5750806 DOI: 10.1080/21505594.2017.1377881] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
An important feature of Mycobacterium tuberculosis pathogenesis is the ability to control cell death in infected host cells, including inhibition of apoptosis and stimulation of necrosis. Recently an alternative form of programmed cell death, necroptosis, has been described where necrotic cell death is induced by apoptotic stimuli under conditions where apoptotic execution is inhibited. We show for the first time that M. tuberculosis and TNFα synergise to induce necroptosis in murine fibroblasts via RIPK1-dependent mechanisms and characterized by phosphorylation of Ser345 of the MLKL necroptosis death effector. However, in murine macrophages M. tuberculosis and TNFα induce non-necroptotic cell death that is RIPK1-dependent but independent of MLKL phosphorylation. Instead, M. tuberculosis-infected macrophages undergo RIPK3-dependent cell death which occurs both in the presence and absence of TNFα and involves the production of mitochondrial ROS. Immunocytochemical staining for MLKL phosphorylation further demonstrated the occurrence of necroptosis in vivo in murine M. tuberculosis granulomas. Phosphorylated-MLKL immunoreactivity was observed associated with the cytoplasm and nucleus of fusiform cells in M. tuberculosis lesions but not in proximal macrophages. Thus whereas pMLKL-driven necroptosis does not appear to be a feature of M. tuberculosis-infected macrophage cell death, it may contribute to TNFα-induced cytotoxicity of the lung stroma and therefore contribute to necrotic cavitation and bacterial dissemination.
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Affiliation(s)
- Rachel E Butler
- a Department of Microbial and Cellular Sciences , Faculty of Health and Medical Sciences, University of Surrey , Guildford , Surrey , UK
| | - Nitya Krishnan
- b MRC Centre for Molecular Bacteriology and Infection , Department of Medicine, Flowers Building, Imperial College London , South Kensington , London , UK
| | - Waldo Garcia-Jimenez
- c Department of Pathology and Infectious Diseases, School of Veterinary Medicine, University of Surrey , Guildford , Surrey , UK
| | - Robert Francis
- a Department of Microbial and Cellular Sciences , Faculty of Health and Medical Sciences, University of Surrey , Guildford , Surrey , UK
| | - Abbe Martyn
- c Department of Pathology and Infectious Diseases, School of Veterinary Medicine, University of Surrey , Guildford , Surrey , UK
| | - Tom Mendum
- a Department of Microbial and Cellular Sciences , Faculty of Health and Medical Sciences, University of Surrey , Guildford , Surrey , UK
| | - Shaza Felemban
- a Department of Microbial and Cellular Sciences , Faculty of Health and Medical Sciences, University of Surrey , Guildford , Surrey , UK
| | - Nicolas Locker
- a Department of Microbial and Cellular Sciences , Faculty of Health and Medical Sciences, University of Surrey , Guildford , Surrey , UK
| | - Francisco J Salguero
- c Department of Pathology and Infectious Diseases, School of Veterinary Medicine, University of Surrey , Guildford , Surrey , UK
| | - Brian Robertson
- b MRC Centre for Molecular Bacteriology and Infection , Department of Medicine, Flowers Building, Imperial College London , South Kensington , London , UK
| | - Graham R Stewart
- a Department of Microbial and Cellular Sciences , Faculty of Health and Medical Sciences, University of Surrey , Guildford , Surrey , UK
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39
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Seveau S, Turner J, Gavrilin MA, Torrelles JB, Hall-Stoodley L, Yount JS, Amer AO. Checks and Balances between Autophagy and Inflammasomes during Infection. J Mol Biol 2017; 430:174-192. [PMID: 29162504 DOI: 10.1016/j.jmb.2017.11.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 11/05/2017] [Accepted: 11/09/2017] [Indexed: 12/24/2022]
Abstract
Autophagy and inflammasome complex assembly are physiological processes that control homeostasis, inflammation, and immunity. Autophagy is a ubiquitous pathway that degrades cytosolic macromolecules or organelles, as well as intracellular pathogens. Inflammasomes are multi-protein complexes that assemble in the cytosol of cells upon detection of pathogen- or danger-associated molecular patterns. A critical outcome of inflammasome assembly is the activation of the cysteine protease caspase-1, which activates the pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18. Studies on chronic inflammatory diseases, heart diseases, Alzheimer's disease, and multiple sclerosis revealed that autophagy and inflammasomes intersect and regulate each other. In the context of infectious diseases, however, less is known about the interplay between autophagy and inflammasome assembly, although it is becoming evident that pathogens have evolved multiple strategies to inhibit and/or subvert these pathways and to take advantage of their intricate crosstalk. An improved appreciation of these pathways and their subversion by diverse pathogens is expected to help in the design of anti-infective therapeutic interventions.
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Affiliation(s)
- Stephanie Seveau
- Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA.
| | - Joanne Turner
- Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Mikhail A Gavrilin
- Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA; Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA
| | | | - Luanne Hall-Stoodley
- Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA
| | - Jacob S Yount
- Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA
| | - Amal O Amer
- Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA
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40
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Moreira-Souza ACA, Almeida-da-Silva CLC, Rangel TP, Rocha GDC, Bellio M, Zamboni DS, Vommaro RC, Coutinho-Silva R. The P2X7 Receptor Mediates Toxoplasma gondii Control in Macrophages through Canonical NLRP3 Inflammasome Activation and Reactive Oxygen Species Production. Front Immunol 2017; 8:1257. [PMID: 29075257 PMCID: PMC5643413 DOI: 10.3389/fimmu.2017.01257] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022] Open
Abstract
Toxoplasma gondii (T. gondii) is the protozoan parasite that causes toxoplasmosis, a potentially fatal disease to immunocompromised patients, and which affects approximately 30% of the world’s population. Previously, we showed that purinergic signaling via the P2X7 receptor contributes to T. gondii elimination in macrophages, through reactive oxygen species (ROS) production and lysosome fusion with the parasitophorous vacuole. Moreover, we demonstrated that P2X7 receptor activation promotes the production of anti-parasitic pro-inflammatory cytokines during early T. gondii infection in vivo. However, the cascade of signaling events that leads to parasite elimination via P2X7 receptor activation remained to be elucidated. Here, we investigated the cellular pathways involved in T. gondii elimination triggered by P2X7 receptor signaling, during early infection in macrophages. We focused on the potential role of the inflammasome, a protein complex that can be co-activated by the P2X7 receptor, and which is involved in the host immune defense against T. gondii infection. Using peritoneal and bone marrow-derived macrophages from knockout mice deficient for inflammasome components (NLRP3−/−, Caspase-1/11−/−, Caspase-11−/−), we show that the control of T. gondii infection via P2X7 receptor activation by extracellular ATP (eATP) depends on the canonical inflammasome effector caspase-1, but not on caspase-11 (a non-canonical inflammasome effector). Parasite elimination via P2X7 receptor and inflammasome activation was also dependent on ROS generation and pannexin-1 channel. Treatment with eATP increased IL-1β secretion from infected macrophages, and this effect was dependent on the canonical NLRP3 inflammasome. Finally, treatment with recombinant IL-1β promoted parasite elimination via mitochondrial ROS generation (as assessed using Mito-TEMPO). Together, our results support a model where P2X7 receptor activation by eATP inhibits T. gondii growth in macrophages by triggering NADPH-oxidase-dependent ROS production, and also by activating a canonical NLRP3 inflammasome, which increases IL-1β production (via caspase-1 activity), leading to mitochondrial ROS generation.
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Affiliation(s)
- Aline Cristina Abreu Moreira-Souza
- Immunobiology Program, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Parasitology and Cell Biology Program, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Thuany Prado Rangel
- Immunobiology Program, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Parasitology and Cell Biology Program, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gabrielle da Costa Rocha
- Immunobiology Program, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria Bellio
- Department of Immunology, Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Dario Simões Zamboni
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Rossiane Claudia Vommaro
- Parasitology and Cell Biology Program, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Robson Coutinho-Silva
- Immunobiology Program, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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41
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Suurväli J, Boudinot P, Kanellopoulos J, Rüütel Boudinot S. P2X4: A fast and sensitive purinergic receptor. Biomed J 2017; 40:245-256. [PMID: 29179879 PMCID: PMC6138603 DOI: 10.1016/j.bj.2017.06.010] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 06/28/2017] [Accepted: 06/30/2017] [Indexed: 01/31/2023] Open
Abstract
Extracellular nucleotides have been recognized as important mediators of activation, triggering multiple responses via plasma membrane receptors known as P2 receptors. P2 receptors comprise P2X ionotropic receptors and G protein-coupled P2Y receptors. P2X receptors are expressed in many tissues, where they are involved in a number of functions including synaptic transmission, muscle contraction, platelet aggregation, inflammation, macrophage activation, differentiation and proliferation, neuropathic and inflammatory pain. P2X4 is one of the most sensitive purinergic receptors (at nanomolar ATP concentrations), about one thousand times more than the archetypal P2X7. P2X4 is widely expressed in central and peripheral neurons, in microglia, and also found in various epithelial tissues and endothelial cells. It localizes on the plasma membrane, but also in intracellular compartments. P2X4 is preferentially localized in lysosomes, where it is protected from proteolysis by its glycosylation. High ATP concentration in the lysosomes does not activate P2X4 at low pH; P2X4 gets activated by intra-lysosomal ATP only in its fully dissociated tetra-anionic form, when the pH increases to 7.4. Thus, P2X4 is functioning as a Ca2+-channel after the fusion of late endosomes and lysosomes. P2X4 modulates major neurotransmitter systems and regulates alcohol-induced responses in microglia. P2X4 is one of the key receptors mediating neuropathic pain. However, injury-induced upregulation of P2X4 expression is gender dependent and plays a key role in pain difference between males and females. P2X4 is also involved in inflammation. Extracellular ATP being a pro-inflammatory molecule, P2X4 can trigger inflammation in response to high ATP release. It is therefore involved in multiple pathologies, like post-ischemic inflammation, rheumatoid arthritis, airways inflammation in asthma, neurodegenerative diseases and even metabolic syndrome. Although P2X4 remains poorly characterized, more studies are needed as it is likely to be a potential therapeutic target in these multiple pathologies.
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Affiliation(s)
- Jaanus Suurväli
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Pierre Boudinot
- Virologie et Immunologie Moléculaires, INRA, Université Paris-Saclay, Jouy-en-Josas, France
| | - Jean Kanellopoulos
- Institute for Integrative Biology of the Cell (I2BC) CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette cedex, France
| | - Sirje Rüütel Boudinot
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.
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42
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Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S. The P2X7 Receptor in Infection and Inflammation. Immunity 2017; 47:15-31. [PMID: 28723547 DOI: 10.1016/j.immuni.2017.06.020] [Citation(s) in RCA: 882] [Impact Index Per Article: 110.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 02/14/2017] [Accepted: 06/27/2017] [Indexed: 12/11/2022]
Abstract
Adenosine triphosphate (ATP) accumulates at sites of tissue injury and inflammation. Effects of extracellular ATP are mediated by plasma membrane receptors named P2 receptors (P2Rs). The P2R most involved in inflammation and immunity is the P2X7 receptor (P2X7R), expressed by virtually all cells of innate and adaptive immunity. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. Ten human P2RX7 gene splice variants and several SNPs that produce complex haplotypes are known. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. However, an in-depth knowledge of its structure and of the associated signal transduction mechanisms is needed for an effective therapeutic development.
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Affiliation(s)
- Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
| | - Diego Dal Ben
- School of Pharmacy, University of Camerino, Camerino, Italy
| | - Alba Clara Sarti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Anna Lisa Giuliani
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Simonetta Falzoni
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
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43
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Petit-Jentreau L, Tailleux L, Coombes JL. Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii. Front Cell Infect Microbiol 2017; 7:347. [PMID: 28824882 PMCID: PMC5545599 DOI: 10.3389/fcimb.2017.00347] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 07/21/2017] [Indexed: 12/15/2022] Open
Abstract
Immune responses are essential for the protection of the host against external dangers or infections and are normally efficient in the clearance of invading microbes. However, some intracellular pathogens have developed strategies to replicate and survive within host cells resulting in latent infection associated with strong inflammation. This excessive response can cause cell and tissue damage and lead to the release of the intracellular content, in particular the nucleotide pool, into the extracellular space. Over the last decade, new studies have implicated metabolites from the purinergic pathway in shaping the host immune response against intracellular pathogens and proved their importance in the outcome of the infection. This review aims to summarize how the immune system employs the purinergic system either to fight the pathogen, or to control collateral tissue damage. This will be achieved by focusing on the macrophage response against two intracellular pathogens, the human etiologic agent of tuberculosis, Mycobacterium tuberculosis and the protozoan parasite, Toxoplasma gondii.
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Affiliation(s)
- Laetitia Petit-Jentreau
- Institute of Infection and Global Health, Department of Infection Biology, University of LiverpoolLiverpool, United Kingdom
| | - Ludovic Tailleux
- Mycobacterial Genetics Unit, Institut PasteurParis, France.,Unit for Integrated Mycobacterial Pathogenomics, Institut PasteurParis, France
| | - Janine L Coombes
- Institute of Infection and Global Health, Department of Infection Biology, University of LiverpoolLiverpool, United Kingdom
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44
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Lam A, Prabhu R, Gross CM, Riesenberg LA, Singh V, Aggarwal S. Role of apoptosis and autophagy in tuberculosis. Am J Physiol Lung Cell Mol Physiol 2017; 313:L218-L229. [PMID: 28495854 DOI: 10.1152/ajplung.00162.2017] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 05/03/2017] [Accepted: 05/03/2017] [Indexed: 01/08/2023] Open
Abstract
Tuberculosis (TB) is one of the oldest known human diseases and is transmitted by the bacteria Mycobacterium tuberculosis (Mtb). TB has a rich history with evidence of TB infections dating back to 5,800 bc TB is unique in its ability to remain latent in an individual for decades, with the possibility of later reactivation, causing widespread systemic symptoms. Currently, it is estimated that more than one-third of the world's population (~2 billion people) are infected with Mtb. Prolonged periods of therapy and complexity of treatment regimens, especially in active infection, have led to poor compliance in patients being treated for TB. Therefore, it is vitally important to have a thorough knowledge of the pathophysiology of Mtb to understand the disease progression, as well as to develop novel diagnostic tests and treatments. Alveolar macrophages represent both the primary host cell and the first line of defense against the Mtb infection. Apoptosis and autophagy of macrophages play a vital role in the pathogenesis and also in the host defense against Mtb. This review will outline the role of these two cellular processes in defense against Mtb with particular emphasis on innate immunity and explore developing therapies aimed at altering host responses to the disease.
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Affiliation(s)
- Adam Lam
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and
| | - Rohan Prabhu
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and
| | | | - Lee Ann Riesenberg
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and
| | - Vinodkumar Singh
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and
| | - Saurabh Aggarwal
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and
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45
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Anti-Mycobacterium avium complex activity of clarithromycin, rifampin, rifabutin, and ethambutol in combination with adenosine 5'-triphosphate. Diagn Microbiol Infect Dis 2017; 88:241-246. [PMID: 28511780 DOI: 10.1016/j.diagmicrobio.2017.04.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 04/18/2017] [Accepted: 04/26/2017] [Indexed: 01/19/2023]
Abstract
We previously reported that adenosine 5'-triphosphate (ATP) inhibited the growth of various bacteria, including mycobacteria, Staphylococcus, and Pseudomonas, without damaging bacterial surface structures. Notably, ATP's antibacterial activity was found to be attributable to its iron-chelating ability. ATP exhibited combined effects with some antimicrobials against Mycobacterium intracellulare and methicillin-resistant S. aureus, suggesting its usefulness as an adjunctive drug in the chemotherapy against certain intractable infections. In this study, we examined detailed profiles of the anti-Mycobacterium avium complex (MAC) activity of some antimicrobial agents, including clarithromycin (CLA), rifampin (RIF), rifabutin (RBT), and ethambutol (EMB), in combination with ATP. It was found that the anti-MAC activity of CLA+RIF, CLA+RBT, and CLA+EMB was markedly potentiated in a strain-dependent manner. In this case, the onset of the regrowth of antimicrobial agent-treated mycobacteria during cultivation was significantly delayed in the presence of ATP, indicating the usefulness of ATP as an adjunctive drug in chemotherapy against MAC infections.
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46
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Abstract
The P2X7 receptor is a trimeric ion channel gated by extracellular adenosine 5'-triphosphate. The receptor is present on an increasing number of different cells types including stem, blood, glial, neural, ocular, bone, dental, exocrine, endothelial, muscle, renal and skin cells. The P2X7 receptor induces various downstream events in a cell-specific manner, including inflammatory molecule release, cell proliferation and death, metabolic events, and phagocytosis. As such this receptor plays important roles in heath and disease. Increasing knowledge about the P2X7 receptor has been gained from studies of, but not limited to, protein chemistry including cloning, site-directed mutagenesis, crystal structures and atomic modeling, as well as from studies of primary tissues and transgenic mice. This chapter focuses on the P2X7 receptor itself. This includes the P2RX7 gene and its products including splice and polymorphic variants. This chapter also reviews modulators of P2X7 receptor activation and inhibition, as well as the transcriptional regulation of the P2RX7 gene via its promoter and enhancer regions, and by microRNA and long-coding RNA. Furthermore, this chapter discusses the post-translational modification of the P2X7 receptor by N-linked glycosylation, adenosine 5'-diphosphate ribosylation and palmitoylation. Finally, this chapter reviews interaction partners of the P2X7 receptor, and its cellular localisation and trafficking within cells.
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Affiliation(s)
- Ronald Sluyter
- School of Biological Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia. .,Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. .,Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.
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47
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Alshammari EM, Mandal RK, Wahid M, Dar SA, Jawed A, Areeshi MY, Khan S, Khan MEA, Panda AK, Haque S. Genetic association study of P2x7 A1513C (rs 3751143) polymorphism and susceptibility to pulmonary tuberculosis: A meta-analysis based on the findings of 11 case–control studies. ASIAN PAC J TROP MED 2016; 9:1150-1157. [DOI: 10.1016/j.apjtm.2016.11.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 08/20/2016] [Accepted: 09/19/2016] [Indexed: 11/16/2022] Open
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48
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López-López C, Jaramillo-Polanco J, Portales-Pérez DP, Gómez-Coronado KS, Rodríguez-Meléndez JG, Cortés-García JD, Espinosa-Luna R, Montaño LM, Barajas-López C. Two P2X1 receptor transcripts able to form functional channels are present in most human monocytes. Eur J Pharmacol 2016; 793:82-88. [PMID: 27823931 DOI: 10.1016/j.ejphar.2016.10.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 10/18/2016] [Accepted: 10/27/2016] [Indexed: 12/24/2022]
Abstract
To characterize the presence and general properties of P2X1 receptors in single human monocytes we used RT-PCR, flow cytometry, and the patch-clamp and the two-electrode voltage-clamp techniques. Most human monocytes expressed the canonical P2X1 (90%) and its splicing variant P2X1del (88%) mRNAs. P2X1 receptor immunoreactivity was also observed in 70% of these cells. Currents mediated by P2X1 (EC50=1.9±0.8µm) and P2X1del (EC50 >1000µm) channels, expressed in Xenopus leavis oocytes, have different ATP sensitivity and kinetics. Both currents mediated by P2X1 and P2X1del channels kept increasing during the continuous presence of high ATP concentrations. Currents mediated by the native P2X1 receptors in human monocytes showed an EC50=6.3±0.2µm. Currents have kinetics that resemble those observed for P2X1 and P2X1del receptors in oocytes. Our study is the first to demonstrate the expression of P2X1 transcript and its splicing variant P2X1del in most human monocytes. We also, for the first time, described functional homomeric P2X1del channels and demonstrated that currents mediated by P2X1 or P2X1del receptors, during heterologous expression, increased in amplitude when activated with high ATP concentrations in a similar fashion to those channels that increase their conductance under similar conditions, such as P2X7, P2X2, and P2X4 channels.
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Affiliation(s)
- Cintya López-López
- Instituto Potosino Investigación Científica y Tecnológica, Camino a la Presa San José 2055, Col. Lomas 4ª Sección, CP 78216, San Luis Potosí, México
| | - Josue Jaramillo-Polanco
- Instituto Potosino Investigación Científica y Tecnológica, Camino a la Presa San José 2055, Col. Lomas 4ª Sección, CP 78216, San Luis Potosí, México
| | | | - Karen S Gómez-Coronado
- Instituto Potosino Investigación Científica y Tecnológica, Camino a la Presa San José 2055, Col. Lomas 4ª Sección, CP 78216, San Luis Potosí, México
| | - Jessica G Rodríguez-Meléndez
- Instituto Potosino Investigación Científica y Tecnológica, Camino a la Presa San José 2055, Col. Lomas 4ª Sección, CP 78216, San Luis Potosí, México
| | - Juan D Cortés-García
- Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, SLP, México
| | - Rosa Espinosa-Luna
- Instituto Potosino Investigación Científica y Tecnológica, Camino a la Presa San José 2055, Col. Lomas 4ª Sección, CP 78216, San Luis Potosí, México
| | - Luis M Montaño
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, México DF, México
| | - Carlos Barajas-López
- Instituto Potosino Investigación Científica y Tecnológica, Camino a la Presa San José 2055, Col. Lomas 4ª Sección, CP 78216, San Luis Potosí, México.
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49
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Pettengill MA, Abdul-Sater A, Coutinho-Silva R, Ojcius DM. Danger signals, inflammasomes, and the intricate intracellular lives of chlamydiae. Biomed J 2016; 39:306-315. [PMID: 27884377 PMCID: PMC6138786 DOI: 10.1016/j.bj.2016.07.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 07/13/2016] [Indexed: 12/20/2022] Open
Abstract
Chlamydiae are obligate intracellular bacterial pathogens, and as such are sensitive to alterations in the cellular physiology of their hosts. Chlamydial infections often cause pathologic consequences due to prolonged localized inflammation. Considerable advances have been made in the last few years regarding our understanding of how two key inflammation-associated signaling pathways influence the biology of Chlamydia infections: inflammation regulating purinergic signaling pathways significantly impact intracellular chlamydial development, and inflammasome activation modulates both chlamydial growth and infection mediated pro-inflammatory cytokine production. We review here elements of both pathways, presenting the latest developments contributing to our understanding of how chlamydial infections are influenced by inflammasomes and purinergic signaling.
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Affiliation(s)
| | - Ali Abdul-Sater
- School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
| | - Robson Coutinho-Silva
- Laboratory of Immunophysiology, Carlos Chagas Filho Biophysics Institute of the Federal University of Rio de Janeiro, Brazil
| | - David M Ojcius
- Laboratory of Immunophysiology, Carlos Chagas Filho Biophysics Institute of the Federal University of Rio de Janeiro, Brazil; Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, USA.
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50
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Surolia R, Karki S, Wang Z, Kulkarni T, Li FJ, Vohra S, Batra H, Nick JA, Duncan SR, Thannickal VJ, Steyn AJC, Agarwal A, Antony VB. Attenuated heme oxygenase-1 responses predispose the elderly to pulmonary nontuberculous mycobacterial infections. Am J Physiol Lung Cell Mol Physiol 2016; 311:L928-L940. [PMID: 27694475 DOI: 10.1152/ajplung.00397.2015] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 09/22/2016] [Indexed: 12/22/2022] Open
Abstract
Pulmonary infections with nontuberculous mycobacteria (P-NTM), such as by Mycobacterium avium complex (M. avium), are increasingly found in the elderly, but the underlying mechanisms are unclear. Recent studies suggest that adaptive immunity is necessary, but not sufficient, for host defense against mycobacteria. Heme oxygenase-1 (HO-1) has been recognized as a critical modulator of granuloma formation and programmed cell death in mycobacterial infections. Old mice (18-21 mo) infected with M. avium had attenuated HO-1 response with diffuse inflammation, high burden of mycobacteria, poor granuloma formation, and decreased survival (45%), while young mice (4-6 mo) showed tight, well-defined granuloma, increased HO-1 expression, and increased survival (95%). To further test the role of HO-1 in increased susceptibility to P-NTM infections in the elderly, we used old and young HO-1+/+ and HO-1-/- mice. The transcriptional modulation of the JAK/STAT signaling pathway in HO-1-/- mice due to M. avium infection demonstrated similarities to infected wild-type old mice with upregulation of SOCS3 and inhibition of Bcl2. Higher expression of SOCS3 with downregulation of Bcl2 resulted in higher macrophage death via cellular necrosis. Finally, peripheral blood monocytes (PBMCs) from elderly patients with P-NTM also demonstrated attenuated HO-1 responses after M. avium stimulation and increased cell death due to cellular necrosis (9.69% ± 2.02) compared with apoptosis (4.75% ± 0.98). The augmented risk for P-NTM in the elderly is due, in part, to attenuated HO-1 responses, subsequent upregulation of SOCS3, and inhibition of Bcl2, leading to programmed cell death of macrophages, and sustained infection.
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Affiliation(s)
- Ranu Surolia
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Suman Karki
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Zheng Wang
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Tejaswini Kulkarni
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Fu Jun Li
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Shikhar Vohra
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Hitesh Batra
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jerry A Nick
- Department of Medicine, National Jewish Health, University of Colorado, Denver, Colorado
| | - Steven R Duncan
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Victor J Thannickal
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama
| | - Adrie J C Steyn
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama.,KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa; and
| | - Anupam Agarwal
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama.,Birmingham VA Medical Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Veena B Antony
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama;
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