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Prado C, Herrada AA, Hevia D, Goiry LG, Escobedo N. Role of innate immune cells in multiple sclerosis. Front Immunol 2025; 16:1540263. [PMID: 40034690 PMCID: PMC11872933 DOI: 10.3389/fimmu.2025.1540263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune, inflammatory and neurodegenerative disease affecting the central nervous system (CNS). MS is associated with a complex interplay between neurodegenerative and inflammatory processes, mostly attributed to pathogenic T and B cells. However, a growing body of preclinical and clinical evidence indicates that innate immunity plays a crucial role in MS promotion and progression. Accordingly, preclinical and clinical studies targeting different innate immune cells to control MS are currently under study, highlighting the importance of innate immunity in this pathology. Here, we reviewed recent findings regarding the role played by innate immune cells in the pathogenesis of MS. Additionally, we discuss potential new treatments for MS based on targets against innate immune components.
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Affiliation(s)
- Carolina Prado
- Laboratorio de Neuroinmunología, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Andrés A. Herrada
- Lymphatic Vasculature and Inflammation Research Laboratory, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
| | - Daniel Hevia
- Center for Studies and Innovation in Dentistry, Facultad de Odontología, Universidad Finis Terrae, Santiago, Chile
| | - Lorna Galleguillos Goiry
- Neurology and Psychiatry Department, Clínica Alemana, Neurology and Neurosurgery Department, Clínica Dávila, Santiago, Chile
| | - Noelia Escobedo
- Lymphatic Vasculature and Inflammation Research Laboratory, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
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Ihedioha OC, Marcarian HQ, Sivakoses A, Beverley SM, McMahon-Pratt D, Bothwell ALM. Leishmania major surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site. Front Immunol 2024; 15:1473133. [PMID: 39502693 PMCID: PMC11534728 DOI: 10.3389/fimmu.2024.1473133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 09/30/2024] [Indexed: 11/08/2024] Open
Abstract
Background Host-related factors highly regulate the increased circulation of neutrophils during Leishmania infection. Platelet-derived Dickkopf-1 (DKK1) is established as a high-affinity ligand to LRP6. Recently, we demonstrated that DKK1 upregulates leukocyte-platelet aggregation, infiltration of neutrophils to the draining lymph node and Th2 differentiation during Leishmania infection, suggesting the potential involvement of the DKK1-LRP6 signalling pathway in neutrophil migration in infectious diseases. Results In this study, we further explored the potential role of DKK1-LRP6 signalling in the migration and longevity of activated neutrophils in the infection site using BALB/c mice with PMNs deficient in LRP6 (LRP6NKO) or BALB/c mice deficient in both PMN LRP6 and platelet DKK1 (LRP6NKO DKK1PKO). Relative to the infected wild-type BALB/c mice, reduced neutrophil activation at the infection site of LRP6NKO or LRP6NKO DKK1PKO mice was noted. The neutrophils obtained from either infected LRP6NKO or LRP6NKO DKK1PKO mice additionally showed a high level of apoptosis. Notably, the level of LRP6 expressing neutrophils was elevated in infected BALB/c mice. Relative to infected BALB/c mice, a significant reduction in parasite load was observed in both LRP6NKO and LRP6NKO DKK1PKO infected mice. Notably, DKK1 levels were comparable in the LRP6NKO and BALB/c mice in response to infection, indicating that PMN activation is the major pathway for DKK1 in promoting parasitemia. Parasite-specific components also play a crucial role in modulating neutrophil circulation in Leishmania disease. Thus, we further determine the contribution of Leishmania membrane components in the migration of neutrophils to the infection site using null mutants deficient in LPG synthesis (Δlpg1- ) or lacking all ether phospholipids (plasmalogens, LPG, and GIPLs) synthesis (Δads1- ). Relative to the WT controls, Δads1- parasite-infected mice showed a sustained decrease in neutrophils and neutrophil-platelet aggregates (for at least 14 days PI), while neutrophils returned to normal in Δlpg1- parasite-infected mice after day 3 PI. Conclusion Our results suggest that DKK1 signalling and Leishmania pathogen-associated molecular patterns appear to regulate the migration and sustenance of viable activated neutrophils in the infection site resulting in chronic type 2 cell-mediated inflammation.
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Affiliation(s)
- Olivia C. Ihedioha
- Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Haley Q. Marcarian
- Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Anutr Sivakoses
- Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Stephen M. Beverley
- Department of Molecular Microbiology, Washington University School of Medicine in St Louis, St. Louis, MO, United States
| | - Diane McMahon-Pratt
- Department of Epidemiology of Infectious Diseases, Yale School of Public Health, New Haven, CT, United States
| | - Alfred L. M. Bothwell
- Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States
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Santamaria JM, Beck CN, Erf GF. Local Inflammatory and Systemic Antibody Responses Initiated by a First Intradermal Administration of Autogenous Salmonella-Killed Vaccines and Their Components in Pullets. Vaccines (Basel) 2024; 12:1159. [PMID: 39460325 PMCID: PMC11511161 DOI: 10.3390/vaccines12101159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/06/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Vaccination strategies are used to manage Salmonella in chickens. Salmonella-killed vaccines are considered safer since they are inactivated. However, little is known regarding the cellular immune activities at the site of vaccine administration of Salmonella-killed vaccines. The growing feather (GF) cutaneous test has been shown to be an effective bioassay to monitor local tissue/cellular responses. We assessed local and systemic antibody responses initiated by intradermal injection of Salmonella-killed vaccines into GF-pulps of 14-15-week-old pullets. Treatments consisted of two autogenous Salmonella-killed vaccines (SV1 and SV2), S. Enteritidis (SE) lipopolysaccharide (SE-LPS), and the water-oil-water (WOW) emulsion vehicle. GF-pulps were collected before (0 h) and at 6, 24, 48, and 72 h post-GF-pulp injection for leukocyte population analysis, while heparinized blood samples were collected before (0 d) and at 3, 5, 7, 10, 14, 21, and 28 d after GF-pulp injections to assess plasma levels (a.u.) of SE-specific IgM, avian IgY (IgG), and IgA antibodies using an ELISA. Injection of GF-pulps with SV1, SV2, or SE-LPS, all in a WOW vehicle, initiated inflammatory responses characterized by the recruitment of heterophils, monocytes/macrophages, and a few lymphocytes. The WOW vehicle emulsion alone recruited more lymphocytes than vaccines or SE-LPS. The SV1 and SV2 vaccines stimulated Salmonella-specific IgM and IgA early, while IgG levels were greatly elevated later during the primary response. Overall, SV1 and SV2 stimulated a heterophil and macrophage-dominated local inflammatory- and SE-specific humoral response with an isotype switch from IgM to IgG, characteristic of a T-dependent primary antibody response. This study provides comprehensive information on innate and adaptive immune responses to autogenous Salmonella-killed vaccines and their components that will find application in the management of Salmonella in poultry.
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Affiliation(s)
- Jossie M. Santamaria
- Department of Poultry Science, Center of Excellence for Poultry Science, University of Arkansas System Division of Agriculture, Fayetteville, AR 72701, USA;
| | | | - Gisela F. Erf
- Department of Poultry Science, Center of Excellence for Poultry Science, University of Arkansas System Division of Agriculture, Fayetteville, AR 72701, USA;
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Choi YJ, Kim Y, Hwang S. Role of Neutrophils in the Development of Steatotic Liver Disease. Semin Liver Dis 2024; 44:300-318. [PMID: 39117322 DOI: 10.1055/s-0044-1789207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
This review explores the biological aspects of neutrophils, their contributions to the development of steatotic liver disease, and their potential as therapeutic targets for the disease. Although alcohol-associated and metabolic dysfunction-associated liver diseases originate from distinct etiological factors, the two diseases frequently share excessive lipid accumulation as a common contributor to their pathogenesis, thereby classifying them as types of steatotic liver disease. Dysregulated lipid deposition in the liver induces hepatic injury, triggering the activation of the innate immunity, partially through neutrophil recruitment. Traditionally recognized for their role in microbial clearance, neutrophils have recently garnered attention for their involvement in sterile inflammation, a pivotal component of steatotic liver disease pathogenesis. In conclusion, technological innovations, including single-cell RNA sequencing, have gradually disclosed the existence of various neutrophil subsets; however, how the distinct subsets of neutrophil population contribute differentially to the development of steatotic liver disease remains unclear.
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Affiliation(s)
- You-Jin Choi
- College of Pharmacy, Daegu Catholic University, Gyeongsan, Republic of Korea
| | - Yeonsoo Kim
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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Moffat A, Gwyer Findlay E. Evidence for antigen presentation by human neutrophils. Blood 2024; 143:2455-2463. [PMID: 38498044 DOI: 10.1182/blood.2023023444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/09/2024] [Indexed: 03/19/2024] Open
Abstract
ABSTRACT Neutrophils are the first migrating responders to sterile and infectious inflammation and act in a powerful but nonspecific fashion to kill a wide variety of pathogens. It is now apparent that they can also act in a highly discriminating fashion; this is particularly evident in their interactions with other cells of the immune system. It is clear that neutrophils are present during the adaptive immune response, interacting with T cells in complex ways that differ between tissue types and disease state. One of the ways in which this interaction is mediated is by neutrophil expression of HLA molecules and presentation of antigen to T cells. In mice, this is well established to occur with both CD4+ and CD8+ T cells. However, the evidence is less strong with human cells. Here, we assembled available evidence for human neutrophil antigen presentation. We find that the human cells are clearly able to upregulate HLA-DR and costimulatory molecules; are able to process protein antigen into fragments recognized by T cells; are able to enter lymph node T cell zones; and, in vitro, are able to present antigen to memory T cells, inducing proliferation and cytokine production. However, many questions remain, particularly concerning whether the cell-cell interactions can last for sufficient time to trigger naïve T cells. These experiments are now critical as we unravel the complex interactions between these cells and their importance for the development of human immunity.
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Affiliation(s)
- Angus Moffat
- School of Biological Sciences, University of Southampton, Southampton, United Kingdom
| | - Emily Gwyer Findlay
- School of Biological Sciences, University of Southampton, Southampton, United Kingdom
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Wu C, Xu J, Zhang Z, Wei D, Xu Y, Zhao Y. The Effects of IL-23/IL-18-Polarized Neutrophils on Renal Ischemia-Reperfusion Injury and Allogeneic-Skin-Graft Rejection in Mice. Biomedicines 2023; 11:3148. [PMID: 38137369 PMCID: PMC10740676 DOI: 10.3390/biomedicines11123148] [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: 09/23/2023] [Revised: 10/26/2023] [Accepted: 11/20/2023] [Indexed: 12/24/2023] Open
Abstract
Neutrophils display heterogeneity and plasticity with different subgroups and immune-regulatory functions under various surrounding conditions. Neutrophils induced by IL-23/IL-18 (referred to N(IL-23+IL-18) neutrophils) have a unique gene-expression profile, with highly expressing IL-17, MHC-II, and costimulatory molecules. The adoptive transfer of N(IL-23+IL-18) neutrophils significantly increased the pathogenesis in a renal ischemia-reperfusion injury mouse model. N(IL-23+IL-18) neutrophils directly and efficiently induced allogeneic T cell proliferation in vitro. N(IL-23+IL-18) neutrophils enhanced the syngeneic T cell response to allogeneic antigens in mixed-lymphocyte reaction assays. The adoptive transfer of the donor or host N(IL-23+IL-18) neutrophils significantly enhanced the antidonor antibody production in an allogeneic-skin-transplanted mouse model, accompanied by increased Tfh cells in the spleens. Therefore, the neutrophil subset induced by IL-23/IL-18 promotes tissue injury and antidonor humoral response in the allogeneic transplantation mouse model.
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Affiliation(s)
- Changhong Wu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Jinglin Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Zhaoqi Zhang
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
| | - Dong Wei
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen 518055, China
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Rambault M, Gilbert FB, Roussel P, Tessier A, David V, Germon P, Winter N, Remot A. Neutrophils expressing major histocompatibility complex class II molecules circulate in blood and milk during mastitis and show high microbicidal activity. J Dairy Sci 2023; 106:4245-4256. [PMID: 37080786 DOI: 10.3168/jds.2022-22728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/23/2022] [Indexed: 04/22/2023]
Abstract
Bovine mastitis is mainly caused by bacterial infection and is responsible for important economic losses as well as alterations of the health and welfare of animals. The increase in somatic cell count (SCC) in milk during mastitis is mainly due to the influx of neutrophils, which have a crucial role in the elimination of pathogens. For a long time, these first-line defenders have been viewed as microbe killers, with a limited role in the orchestration of the immune response. However, their role is more complex: we recently characterized a bovine neutrophil subset expressing major histocompatibility complex class II (MHC-II) molecules (MHC-IIpos), usually distributed on antigen-presenting cells, as having regulatory capacities in cattle. In this study, our objective was to evaluate the implication of different neutrophils subsets in the mammary gland immunity during clinical and subclinical mastitis. Using flow cytometry, we analyzed the presence of MHC-IIpos neutrophils in blood and in milk during clinical mastitis at different time points of inflammation (n = 10 infected quarters) and during subclinical mastitis, defined as the presence of bacteria and an SCC >150,000 cells/mL (n = 27 infected quarters). Our results show, for the first time, that in blood and milk, neutrophils are a heterogeneous population and encompass at least 2 subsets distinguishable by their expression of MHC-II. In milk without mastitis, we observed higher production of reactive oxygen species and higher phagocytosis capacity of MHC-IIpos neutrophils compared with their MHC-IIneg counterparts, indicating the high bactericidal capacities of MHC-IIpos neutrophils. MHC-IIpos neutrophils are enriched in milk compared with blood during subclinical mastitis but not during clinical mastitis. Moreover, we observed a positive and highly significant correlation between MHC-IIpos neutrophils and T lymphocytes present in milk during subclinical mastitis. Our experiments involved a total of 47 cows (40 Holstein and 7 Normande cows). To conclude, our study opens the way to the discovery of new biomarkers of mastitis inflammation.
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Affiliation(s)
- Marion Rambault
- INRAE, UMR ISP, 37380, Nouzilly, France; Institut de l'élevage, 75012, Paris, France
| | | | | | | | | | | | | | - Aude Remot
- INRAE, UMR ISP, 37380, Nouzilly, France.
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Hussen J, Alkuwayti MA, Falemban B, Alhojaily SM, Adwani SA, Hassan EAE, Al-Mubarak AIA. Impact of Selected Bacterial and Viral Toll-like Receptor Agonists on the Phenotype and Function of Camel Blood Neutrophils. Vet Sci 2023; 10:154. [PMID: 36851458 PMCID: PMC9963015 DOI: 10.3390/vetsci10020154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Innate recognition of pathogens depends on the interaction between microbial structures known as pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) in host cells. Toll-like receptors (TLR) are among the most important PRRs being expressed on and in a wide range of immune cell types. Studies on the interaction mechanisms between different pathogen species and the immune system of the dromedary camel are still scarce. The present study aimed to investigate the immunomodulatory effect of synthetic bacterial and viral TLR ligands on some phenotypic properties and selected functions of neutrophils purified from dromedary camel blood. Neutrophils were separated from camel blood (n = five animals) and were stimulated in vitro with the TLR ligands LPS, Pam3CSK4, R848 (Resiquimod), and Poly IC or were left without stimulation. Stimulation with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) was used as a positive control stimulation. Shape change, phagocytosis activity, ROS production, the expression of cell surface markers, and cell vitality were compared between stimulated and non-stimulated cells. With exception of the TLR3 agonist Poly IC, all TLR ligands used showed the potential to stimulate camel neutrophils resulting in increased cell size and the upregulation of CD18 and CD14 on their surface. Similarly, the phagocytosis activity of camel neutrophils was significantly improved after priming with all TLR ligands, except Poly IC, which, in contrast, resulted in a reduced percentage of phagocytosis-positive cells. In contrast to stimulation with PMA, which induced a significant ROS production in camel neutrophils, none of the TLR ligands used stimulated ROS generation in neutrophils. Only stimulation with Pam3CSK4 increased the expression of MHCII molecules on camel neutrophils, resulting in an expanded MHCIIhigh fraction within camel neutrophils. Our study indicates selective immunomodulating effects of TLR agonists on purified camel neutrophils without affecting their vitality.
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Affiliation(s)
- Jamal Hussen
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | | | - Baraa Falemban
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Sameer M. Alhojaily
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Agricultural and Veterinary Training and Research Station, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Salma Al Adwani
- Department of Animal & Veterinary Sciences, Sultan Qaboos University, Muscat 123, Oman
| | - El Awad El Hassan
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Abdullah IA Al-Mubarak
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
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Shen P, Rother M, Stervbo U, Lampropoulou V, Calderon-Gomez E, Roch T, Hilgenberg E, Ries S, Kühl AA, Jouneau L, Boudinot P, Fillatreau S. Toll-like receptors control the accumulation of neutrophils in lymph nodes that expand CD4 + T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 2023; 53:e2250059. [PMID: 36458588 PMCID: PMC10107244 DOI: 10.1002/eji.202250059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 11/10/2022] [Accepted: 11/30/2022] [Indexed: 12/04/2022]
Abstract
Toll-like receptors (TLR) control the activation of dendritic cells that prime CD4+ T cells in draining lymph nodes, where these T cells then undergo massive clonal expansion. The mechanisms controlling this clonal T cell expansion are poorly defined. Using the CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis (EAE), we show here that this process is markedly suppressed when TLR9 signaling is increased, without noticeably affecting the transcriptome of primed T cells, indicating a purely quantitative effect on CD4+ T cell expansion. Addressing the underpinning mechanisms revealed that CD4+ T cell expansion was preceded and depended on the accumulation of neutrophils in lymph nodes a few days after immunization. Underlying the importance of this immune regulation pathway, blocking neutrophil accumulation in lymph nodes by treating mice with a TLR9 agonist inhibited EAE progression in mice with defects in regulatory T cells or regulatory B cells, which otherwise developed a severe chronic disease. Collectively, this study demonstrates the key role of neutrophils in the quantitative regulation of antigen-specific CD4+ T cell expansion in lymph nodes, and the counter-regulatory role of TLR signaling in this process.
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Affiliation(s)
- Ping Shen
- Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Germany.,Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117, Berlin, Germany.,Stem Cell and Biotherapy Engineering Research Center of Henan Province, College of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Madlen Rother
- Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Germany
| | - Ulrik Stervbo
- Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Germany
| | - Vicky Lampropoulou
- Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Germany.,Department of Microbiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Toralf Roch
- Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Germany
| | - Ellen Hilgenberg
- Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Germany
| | - Steffi Ries
- Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Germany
| | - Anja A Kühl
- Institute of Pathology/RCIS, Charité, Campus Benjamin Franklin, 12203, Berlin, Germany
| | - Luc Jouneau
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, 78350, France
| | - Pierre Boudinot
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, 78350, France
| | - Simon Fillatreau
- Deutsches Rheumaforschungszentrum Berlin, a Leibniz Institute, Germany.,Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Paris, F-75015, France.,Service Immunologie Biologique, AP-HP, Hôpital Necker-Enfants Malades, Paris, F-75015, France
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10
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Haugland GT, Rønneseth A, Gundersen L, Lunde HS, Nordland K, Wergeland HI. Neutrophils in Atlantic salmon (Salmo salar L.) are MHC class II+ and secret IL-12p40 upon bacterial exposure. AQUACULTURE AND FISHERIES 2022. [DOI: 10.1016/j.aaf.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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11
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Lee HY, You DJ, Taylor-Just AJ, Linder KE, Atkins HM, Ralph LM, De la Cruz G, Bonner JC. Pulmonary exposure of mice to ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX) suppresses the innate immune response to carbon black nanoparticles and stimulates lung cell proliferation. Inhal Toxicol 2022; 34:244-259. [PMID: 35704474 DOI: 10.1080/08958378.2022.2086651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Per- and polyfluoroalkyl substances (PFAS) have been associated with respiratory diseases in humans, yet the mechanisms through which PFAS cause susceptibility to inhaled agents is unknown. Herein, we investigated the effects of ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), an emerging PFAS, on the pulmonary immune response of mice to carbon black nanoparticles (CBNP). We hypothesized that pulmonary exposure to GenX would increase susceptibility to CBNP through suppression of innate immunity. METHODS Male C57BL/6 mice were exposed to vehicle, 4 mg/kg CBNP, 10 mg/kg GenX, or CBNP and GenX by oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) was collected at 1 and 14 days postexposure for cytokines and total protein. Lung tissue was harvested for histopathology, immunohistochemistry (Ki67 and phosphorylated (p)-STAT3), western blotting (p-STAT3 and p-NF-κB), and qRT-PCR for cytokine mRNAs. RESULTS CBNP increased CXCL-1 and neutrophils in BALF at both time points evaluated. However, GenX/CBNP co-exposure reduced CBNP-induced CXCL-1 and neutrophils in BALF. Moreover, CXCL-1, CXCL-2 and IL-1β mRNAs were increased by CBNP in lung tissue but reduced by GenX. Western blotting showed that CBNP induced p-NF-κB in lung tissue, while the GenX/CBNP co-exposed group displayed decreased p-NF-κB. Furthermore, mice exposed to GenX or GenX/CBNP displayed increased numbers of BALF macrophages undergoing mitosis and increased Ki67 immunostaining. This was correlated with increased p-STAT3 by western blotting and immunohistochemistry in lung tissue from mice co-exposed to GenX/CBNP. CONCLUSIONS Pulmonary exposure to GenX suppressed CBNP-induced innate immune response in the lungs of mice yet promoted the proliferation of macrophages and lung epithelial cells.
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Affiliation(s)
- Ho Young Lee
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Dorothy J You
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Alexia J Taylor-Just
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Keith E Linder
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA
| | - Hannah M Atkins
- Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA.,Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Lauren M Ralph
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Gabriela De la Cruz
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - James C Bonner
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
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12
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Guenther C. β2-Integrins - Regulatory and Executive Bridges in the Signaling Network Controlling Leukocyte Trafficking and Migration. Front Immunol 2022; 13:809590. [PMID: 35529883 PMCID: PMC9072638 DOI: 10.3389/fimmu.2022.809590] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Abstract
Leukocyte trafficking is an essential process of immunity, occurring as leukocytes travel within the bloodstream and as leukocyte migration within tissues. While it is now established that leukocytes can utilize the mesenchymal migration mode or amoeboid migration mode, differences in the migratory behavior of leukocyte subclasses and how these are realized on a molecular level in each subclass is not fully understood. To outline these differences, first migration modes and their dependence on parameters of the extracellular environments will be explained, as well as the intracellular molecular machinery that powers migration in general. Extracellular parameters are detected by adhesion receptors such as integrins. β2-integrins are surface receptors exclusively expressed on leukocytes and are essential for leukocytes exiting the bloodstream, as well as in mesenchymal migration modes, however, integrins are dispensable for the amoeboid migration mode. Additionally, the balance of different RhoGTPases - which are downstream of surface receptor signaling, including integrins - mediate formation of membrane structures as well as actin dynamics. Individual leukocyte subpopulations have been shown to express distinct RhoGTPase profiles along with their differences in migration behavior, which will be outlined. Emerging aspects of leukocyte migration include signal transduction from integrins via actin to the nucleus that regulates DNA status, gene expression profiles and ultimately leukocyte migratory phenotypes, as well as altered leukocyte migration in tumors, which will be touched upon.
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Affiliation(s)
- Carla Guenther
- Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
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13
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Anti-PD-1 Therapy with Adjuvant Ablative Fractional Laser Improves Anti-Tumor Response in Basal Cell Carcinomas. Cancers (Basel) 2021; 13:cancers13246326. [PMID: 34944945 PMCID: PMC8699063 DOI: 10.3390/cancers13246326] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/08/2021] [Accepted: 12/14/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary In some mouse models, ablative fractional laser (AFL) enhances the efficacy of anti-programmed cell death1 therapy (aPD-1), which was recently approved for basal cell carcinoma (BCC). In this explorative study, we aimed to assess locally applied AFL as an adjuvant to systemic aPD-1 treatment in a clinically relevant BCC model. BCC-carrying mice received aPD-1 alone, AFL alone, aPD-1+AFL, or no treatment. Both aPD-1 and AFL alone significantly increased survival time relative to the untreated controls, while aPD-1 that had been complemented with AFL further promoted survival and improved tumor clearance and growth rates. The BCCs were poorly immune infiltrated, but aPD-1 with adjuvant AFL and AFL alone induced substantial immune cell infiltration in tumors and increased the levels of relevant immune cell subtypes. Thus, the anti-tumor response that was generated by aPD-1 with adjuvant AFL may potentially be promoted by increased immune activity in tumors. In conclusion, the use of a local AFL adjuvant to systemic aPD-1 therapy could hold substantial promise for BCC treatment. Abstract The efficacy of anti-programmedcelldeath1therapy (aPD-1), which was recently approved for basal cell carcinoma (BCC) treatment, can be enhanced by adjuvant ablative fractional laser (AFL) in syngeneic murine tumor models. In this explorative study, we aimed to assess locally applied AFL as an adjuvant to systemic aPD-1 treatment in a clinically relevant autochthonous BCC model. BCC tumors (n = 72) were induced in Ptch1+/−K14-CreER2p53fl/fl-mice (n = 34), and the mice subsequently received aPD-1 alone, AFL alone, aPD-1+AFL, or no treatment. The outcome measures included mouse survival time, tumor clearance, tumor growth rates, and tumor immune infiltration. Both aPD-1 and AFL alone significantly increased survival time relative to untreated controls (31 d and 34.5 d, respectively vs. 14 d, p = 0.0348–0.0392). Complementing aPD-1 with AFL further promoted survival (60 d, p = 0.0198 vs. aPD-1) and improved tumor clearance and growth rates. The BCCs were poorly immune infiltrated, but aPD-1 with adjuvant AFL and AFL alone induced substantial immune cell infiltration in the tumors. Similar to AFL alone, combined aPD-1 and AFL increased neutrophil counts (4-fold, p = 0.0242), the proportion of MHCII-positive neutrophils (p = 0.0121), and concordantly, CD4+ and CD8+ T-cell infiltration (p = 0.0061–0.0242). These descriptive results suggest that the anti-tumor response that is generated by aPD-1 with adjuvant AFL is potentially promoted by increased neutrophil and T-cell engraftment in tumors. In conclusion, local AFL shows substantial promise as an adjuvant to systemic aPD-1 therapy in a clinically relevant preclinical BCC model.
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14
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Lok LSC, Clatworthy MR. Neutrophils in secondary lymphoid organs. Immunology 2021; 164:677-688. [PMID: 34411302 PMCID: PMC8561103 DOI: 10.1111/imm.13406] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/02/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
Neutrophils are traditionally considered short‐lived, circulating innate immune cells that are rapidly recruited to sites of inflammation in response to infectious and inflammatory stimuli. Neutrophils efficiently internalize, kill or entrap pathogens, but their effector molecules may cause collateral tissue damage. More recently, it has been appreciated that neutrophils can also influence adaptive immunity. Lymph nodes (LNs) are immune cell‐rich secondary lymphoid organs that provide an ideal platform for cellular interaction and the integration of immunological information collected from local tissues. A variety of peripheral stimuli promote neutrophil migration to draining LNs via blood or lymphatics, utilizing differing molecular cues depending on the site of entry. Within LNs, neutrophils interact with other innate and adaptive cells. Crosstalk with subcapsular sinus macrophages contributes to the control of pathogen spread beyond the LN. Neutrophils can influence antigen presentation indirectly by interacting with DCs or directly by expressing major histocompatibility complex (MHC) and costimulatory molecules for antigen presentation. Interactions between neutrophils and adaptive lymphocytes can alter B‐cell antibody responses. Studies have shown conflicting results on whether neutrophils exert stimulatory or inhibitory effects on other LN immune cells, with stimulus‐specific and temporal differences in the outcome of these interactions. Furthermore, neutrophils have also been shown to traffick to LNs in homeostasis, with a potential role in immune surveillance, antigen capture and in shaping early adaptive responses in LNs. Understanding the mechanisms underpinning the effects of neutrophils on LN immune cells and adaptive immunity could facilitate the development of neutrophil‐targeted therapies in inflammatory diseases.
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Affiliation(s)
- Laurence S C Lok
- Molecular Immunity Unit, MRC Laboratory of Molecular Biology, University of Cambridge Department of Medicine, Cambridge, UK.,Cambridge Institute for Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge, UK.,Department of Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan.,Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Menna R Clatworthy
- Molecular Immunity Unit, MRC Laboratory of Molecular Biology, University of Cambridge Department of Medicine, Cambridge, UK.,Cambridge Institute for Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge, UK.,Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
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15
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Mysore V, Cullere X, Mears J, Rosetti F, Okubo K, Liew PX, Zhang F, Madera-Salcedo I, Rosenbauer F, Stone RM, Aster JC, von Andrian UH, Lichtman AH, Raychaudhuri S, Mayadas TN. FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity. Nat Commun 2021; 12:4791. [PMID: 34373452 PMCID: PMC8352912 DOI: 10.1038/s41467-021-24591-x] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8+ T cell-dependent anti-tumor immunity in mice. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, blood nAPC frequency in lupus patients correlates with disease. Moreover, anti-FcγRIIIB-antigen conjugate treatment induces nAPCs that can activate autologous T cells when using neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those vaccinated against bacterial toxins. Thus, anti-FcγRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a possible immunotherapy for cancer and infectious diseases.
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Affiliation(s)
- Vijayashree Mysore
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Xavier Cullere
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Joseph Mears
- Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Florencia Rosetti
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Koshu Okubo
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Pei X Liew
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Fan Zhang
- Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Iris Madera-Salcedo
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Frank Rosenbauer
- Institute of Molecular Tumor Biology, University of Muenster, Muenster, Germany
| | - Richard M Stone
- Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Jon C Aster
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ulrich H von Andrian
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - Andrew H Lichtman
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Soumya Raychaudhuri
- Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK
| | - Tanya N Mayadas
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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16
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The Role of Neutrophil Extracellular Traps in Central Nervous System Diseases and Prospects for Clinical Application. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9931742. [PMID: 34336122 PMCID: PMC8294981 DOI: 10.1155/2021/9931742] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 07/01/2021] [Indexed: 12/13/2022]
Abstract
Neutrophil extracellular traps (NETs) are complexes of decondensed DNA fibers and antimicrobial peptides that are released by neutrophils and play important roles in many noninfectious diseases, such as cystic fibrosis, systemic lupus erythematosus, diabetes, and cancer. Recently, the formation of NETs has been detected in many central nervous system diseases and is thought to play different roles in the occurrence and development of these diseases. Researchers have detected NETs in acute ischemic stroke thrombi, and these NETs are thought to promote coagulation and thrombosis. NETs in ischemic brain parenchyma were identified as the cause of secondary nerve damage. High levels of NETs were also detected in grade IV glioma tissues, where NETs were involved in the proliferation and invasion of glioma cells by activating a signaling pathway. Extracellular web-like structures have also recently been observed in mice with traumatic brain injury (TBI), and it was hypothesized that NETs contribute to the development of edema after TBI. This article reviews the effect of NETs on multiple diseases that affect the CNS and explores their clinical application prospects.
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17
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Johansson C, Kirsebom FCM. Neutrophils in respiratory viral infections. Mucosal Immunol 2021; 14:815-827. [PMID: 33758367 PMCID: PMC7985581 DOI: 10.1038/s41385-021-00397-4] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 02/04/2023]
Abstract
Viral respiratory infections are a common cause of severe disease, especially in infants, people who are immunocompromised, and in the elderly. Neutrophils, an important innate immune cell, infiltrate the lungs rapidly after an inflammatory insult. The most well-characterized effector mechanisms by which neutrophils contribute to host defense are largely extracellular and the involvement of neutrophils in protection from numerous bacterial and fungal infections is well established. However, the role of neutrophils in responses to viruses, which replicate intracellularly, has been less studied. It remains unclear whether and, by which underlying immunological mechanisms, neutrophils contribute to viral control or confer protection against an intracellular pathogen. Furthermore, neutrophils need to be tightly regulated to avoid bystander damage to host tissues. This is especially relevant in the lung where damage to delicate alveolar structures can compromise gas exchange with life-threatening consequences. It is inherently less clear how neutrophils can contribute to host immunity to viruses without causing immunopathology and/or exacerbating disease severity. In this review, we summarize and discuss the current understanding of how neutrophils in the lung direct immune responses to viruses, control viral replication and spread, and cause pathology during respiratory viral infections.
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Affiliation(s)
- Cecilia Johansson
- National Heart and Lung Institute, Imperial College London, London, UK.
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18
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Singh RP, Hahn BH, Bischoff DS. Effects of Peptide-Induced Immune Tolerance on Murine Lupus. Front Immunol 2021; 12:662901. [PMID: 34093553 PMCID: PMC8171184 DOI: 10.3389/fimmu.2021.662901] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/28/2021] [Indexed: 12/18/2022] Open
Abstract
The regulation of autoimmunity and the molecular mechanisms by which different immune cells, including T cells, polymorphonuclear leukocytes (PMN-granulocytes), and B cells suppress autoimmune diseases is complex. We have shown previously that BWF1 lupus mice are protected from autoimmunity after i.v. injection or oral administration of tolerogenic doses of pCons, an artificial synthetic peptide based on sequences containing MHC class I and MHC class II determinants in the VH region of a J558-encoded BWF1 anti-DNA Ab. Several T cell subsets can transfer this tolerance. In this study, we determined the potential roles of granulocytes, B cells and regulatory T cells altered by pCons treatment in the BWF1 (NZB/NZW) mouse model of lupus. Immunophenotyping studies indicated that pCons treatment of BWF1 mice significantly increased CD4+FoxP3+ T cells, reduced the percent of B cells expressing CD19+CD5+ but increased the percent of CD19+CD1d+ regulatory B cells and increased the ability of the whole B cell population to suppress IgG anti-DNA production in vitro. pCons treatment significantly decreased the expression of CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) in CD8+ T cells. In addition, peptide administration modified granulocytes so they became suppressive. We co-cultured sorted naïve B cells from mice making anti-DNA Ab (supported by addition of sorted naive CD4+ and CD8+ T cells from young auto-antibody-negative BWF1 mice) with sorted B cells or granulocytes from tolerized mice. Both tolerized granulocytes and tolerized B cells significantly suppressed the production of anti-DNA in vitro. In granulocytes from tolerized mice compared to saline-treated littermate controls, real-time PCR analysis indicated that expression of interferon-induced TNFAIP2 increased more than 2-fold while Ptdss2 and GATA1 mRNA were up-regulated more than 10-fold. In contrast, expression of these genes was significantly down-regulated in tolerized B cells. Further, another IFN-induced protein, Bcl2, was reduced in tolerized B cells as determined by Western blot analyses. In contrast, expression of FoxP3 was significantly increased in tolerized B cells. Together, these data suggest that B cells and granulocytes are altered toward suppressive functions by in vivo tolerization of BWF1 mice with pCons and it is possible these cell types participate in the clinical benefits seen in vivo.
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Affiliation(s)
- Ram P Singh
- Research Service, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA, United States.,Division of Rheumatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Bevra H Hahn
- Division of Rheumatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - David S Bischoff
- Research Service, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA, United States.,Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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19
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Cerezo-Wallis D, Ballesteros I. Neutrophils in cancer, a love-hate affair. FEBS J 2021; 289:3692-3703. [PMID: 33999496 DOI: 10.1111/febs.16022] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/05/2021] [Accepted: 05/14/2021] [Indexed: 11/30/2022]
Abstract
Neutrophils dominate the immunological landscape of multiple types of solid tumours in mice and humans and exert different pro- or antitumoral activity. This functional heterogeneity has prompted a search for different subsets and classifications of tumour-infiltrating neutrophils with the idea of better delineating their specific roles in cancer. In this review, we describe current studies that highlight specific mechanisms by which neutrophils exert pro- or antitumoral function and focus on how distinct tumour types induce unique functional states in neutrophils, co-opt granulopoiesis, modulate neutrophil ageing and prolong the neutrophil life span. In addition, we discuss how the tissue-specific tumour stroma and the stage of the cancer influence the function and number of tumour-infiltrating neutrophils. Finally, we explore different approaches to enhance the therapeutic efficacy in cancer types dominated by neutrophils.
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Affiliation(s)
- Daniela Cerezo-Wallis
- Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Iván Ballesteros
- Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
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20
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In Sickness and in Health: The Immunological Roles of the Lymphatic System. Int J Mol Sci 2021; 22:ijms22094458. [PMID: 33923289 PMCID: PMC8123157 DOI: 10.3390/ijms22094458] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/15/2021] [Accepted: 04/18/2021] [Indexed: 02/06/2023] Open
Abstract
The lymphatic system plays crucial roles in immunity far beyond those of simply providing conduits for leukocytes and antigens in lymph fluid. Endothelial cells within this vasculature are distinct and highly specialized to perform roles based upon their location. Afferent lymphatic capillaries have unique intercellular junctions for efficient uptake of fluid and macromolecules, while expressing chemotactic and adhesion molecules that permit selective trafficking of specific immune cell subsets. Moreover, in response to events within peripheral tissue such as inflammation or infection, soluble factors from lymphatic endothelial cells exert “remote control” to modulate leukocyte migration across high endothelial venules from the blood to lymph nodes draining the tissue. These immune hubs are highly organized and perfectly arrayed to survey antigens from peripheral tissue while optimizing encounters between antigen-presenting cells and cognate lymphocytes. Furthermore, subsets of lymphatic endothelial cells exhibit differences in gene expression relating to specific functions and locality within the lymph node, facilitating both innate and acquired immune responses through antigen presentation, lymph node remodeling and regulation of leukocyte entry and exit. This review details the immune cell subsets in afferent and efferent lymph, and explores the mechanisms by which endothelial cells of the lymphatic system regulate such trafficking, for immune surveillance and tolerance during steady-state conditions, and in response to infection, acute and chronic inflammation, and subsequent resolution.
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21
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Bhattacharya P, Dey R, Saxena A, Karmakar S, Ismail N, Gannavaram S, Dagur PK, Satoskar M, Satoskar S, De Paoli S, Takeda K, McCoy JP, Nakhasi HL. Essential Role of Neutrophils in the Protective Immune Response Induced by a Live Attenuated Leishmania Vaccine. THE JOURNAL OF IMMUNOLOGY 2020; 205:3333-3347. [PMID: 33177159 DOI: 10.4049/jimmunol.2000829] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/01/2020] [Indexed: 12/13/2022]
Abstract
No licensed vaccine exists against visceral leishmaniasis (VL), a disease caused by the Leishmania donovani parasite. We have previously reported both macrophages and dendritic cells play important role in the protection induced by a live attenuated centrin gene-deleted L. donovani (LdCen-/- ) parasite vaccine. The role of neutrophils in orchestrating the initial innate response to pathogens is widely recognized. To investigate the early interaction of LdCen-/- with neutrophils, we immunized mice intradermally in the ear pinna with LdCen-/- Compared with LdWT infection, LdCen-/- parasites induced higher recruitment of neutrophils to the ear dermis and ear draining lymph nodes (dLN) as early as 6-18 h after immunization, which were predominantly proinflammatory in nature. Neutrophils from ear dLN of LdCen-/- -immunized mice exhibited heightened expression of costimulatory molecules and attenuated expression of coinhibitory molecules necessary for higher T cell activation. Further phenotypic characterization revealed heterogeneous neutrophil populations containing Nα and Nβ subtypes in the ear dLN. Of the two, the parasitized Nα subset from LdCen-/- -immunized mice exhibited much stronger Ag-specific CD4+ T cell proliferation ex vivo. Adoptive transfer of neutrophils bearing LdCen-/- parasites induced an increased Th1 response in naive mice. Importantly, neutrophil depletion significantly abrogated Ag-specific CD4+ T cell proliferation in LdCen-/- -immunized mice and impaired protection against virulent challenge. Conversely, replenishing of neutrophils significantly restored the LdCen-/- -induced host-protective response. These results suggest that neutrophils are indispensable for protective immunity induced by LdCen-/- parasite vaccine.
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Affiliation(s)
- Parna Bhattacharya
- Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993;
| | - Ranadhir Dey
- Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993
| | - Ankit Saxena
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
| | - Subir Karmakar
- Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993
| | - Nevien Ismail
- Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993
| | - Sreenivas Gannavaram
- Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993
| | - Pradeep K Dagur
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
| | | | | | - Silvia De Paoli
- Office of Blood Research and Review, U.S. Food and Drug Administration, Silver Spring, MD 20993; and
| | - Kazuyo Takeda
- Microscopy and Imaging Core Facility, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993
| | - John Philip McCoy
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
| | - Hira L Nakhasi
- Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993;
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22
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Ustyanovska Avtenyuk N, Visser N, Bremer E, Wiersma VR. The Neutrophil: The Underdog That Packs a Punch in the Fight against Cancer. Int J Mol Sci 2020; 21:E7820. [PMID: 33105656 PMCID: PMC7659937 DOI: 10.3390/ijms21217820] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/19/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023] Open
Abstract
The advent of immunotherapy has had a major impact on the outcome and overall survival in many types of cancer. Current immunotherapeutic strategies typically aim to (re)activate anticancer T cell immunity, although the targeting of macrophage-mediated anticancer innate immunity has also emerged in recent years. Neutrophils, although comprising ≈ 60% of all white blood cells in the circulation, are still largely overlooked in this respect. Nevertheless, neutrophils have evident anticancer activity and can induce phagocytosis, trogocytosis, as well as the direct cytotoxic elimination of cancer cells. Furthermore, therapeutic tumor-targeting monoclonal antibodies trigger anticancer immune responses through all innate Fc-receptor expressing cells, including neutrophils. Indeed, the depletion of neutrophils strongly reduced the efficacy of monoclonal antibody treatment and increased tumor progression in various preclinical studies. In addition, the infusion of neutrophils in murine cancer models reduced tumor progression. However, evidence on the anticancer effects of neutrophils is fragmentary and mostly obtained in in vitro assays or murine models with reports on anticancer neutrophil activity in humans lagging behind. In this review, we aim to give an overview of the available knowledge of anticancer activity by neutrophils. Furthermore, we will describe strategies being explored for the therapeutic activation of anticancer neutrophil activity.
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Affiliation(s)
| | | | - Edwin Bremer
- Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen (UMCG), University of Groningen, Hanzeplein 1/DA13, 9713 GZ Groningen, The Netherlands; (N.U.A.); (N.V.)
| | - Valerie R. Wiersma
- Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen (UMCG), University of Groningen, Hanzeplein 1/DA13, 9713 GZ Groningen, The Netherlands; (N.U.A.); (N.V.)
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23
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Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome. Mol Psychiatry 2020; 25:2567-2583. [PMID: 31092898 DOI: 10.1038/s41380-019-0425-1] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 03/23/2019] [Accepted: 03/26/2019] [Indexed: 12/12/2022]
Abstract
Male middle age is a transitional period where many physiological and psychological changes occur leading to cognitive and behavioural alterations, and a deterioration of brain function. However, the mechanisms underpinning such changes are unclear. The gut microbiome has been implicated as a key mediator in the communication between the gut and the brain, and in the regulation of brain homeostasis, including brain immune cell function. Thus, we tested whether targeting the gut microbiome by prebiotic supplementation may alter microglia activation and brain function in ageing. Male young adult (8 weeks) and middle-aged (10 months) C57BL/6 mice received diet enriched with a prebiotic (10% oligofructose-enriched inulin) or control chow for 14 weeks. Prebiotic supplementation differentially altered the gut microbiota profile in young and middle-aged mice with changes correlating with faecal metabolites. Functionally, this translated into a reversal of stress-induced immune priming in middle-aged mice. In addition, a reduction in ageing-induced infiltration of Ly-6Chi monocytes into the brain coupled with a reversal in ageing-related increases in a subset of activated microglia (Ly-6C+) was observed. Taken together, these data highlight a potential pathway by which targeting the gut microbiome with prebiotics can modulate the peripheral immune response and alter neuroinflammation in middle age. Our data highlight a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.
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De Bondt M, Hellings N, Opdenakker G, Struyf S. Neutrophils: Underestimated Players in the Pathogenesis of Multiple Sclerosis (MS). Int J Mol Sci 2020; 21:E4558. [PMID: 32604901 PMCID: PMC7349048 DOI: 10.3390/ijms21124558] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 01/06/2023] Open
Abstract
Neutrophils are the most abundant circulating and first-responding innate myeloid cells and have so far been underestimated in the context of multiple sclerosis (MS). MS is the most frequent, immune-mediated, inflammatory disease of the central nervous system. MS is treatable but not curable and its cause(s) and pathogenesis remain elusive. The involvement of neutrophils in MS pathogenesis has been suggested by the use of preclinical animal disease models, as well as on the basis of patient sample analysis. In this review, we provide an overview of the possible mechanisms and functions by which neutrophils may contribute to the development and pathology of MS. Neutrophils display a broad variety of effector functions enabling disease pathogenesis, including (1) the release of inflammatory mediators and enzymes, such as interleukin-1β, myeloperoxidase and various proteinases, (2) destruction and phagocytosis of myelin (as debris), (3) release of neutrophil extracellular traps, (4) production of reactive oxygen species, (5) breakdown of the blood-brain barrier and (6) generation and presentation of autoantigens. An important question relates to the issue of whether neutrophils exhibit a predominantly proinflammatory function or are also implicated in the resolution of chronic inflammatory responses in MS.
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Affiliation(s)
- Mirre De Bondt
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49—Box 1042, 3000 Leuven, Belgium;
- Neuro Immune Connections & Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium;
| | - Niels Hellings
- Neuro Immune Connections & Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium;
| | - Ghislain Opdenakker
- Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49—Box 1044, 3000 Leuven, Belgium;
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49—Box 1042, 3000 Leuven, Belgium;
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25
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Ballegeer M, Saelens X. Cell-Mediated Responses to Human Metapneumovirus Infection. Viruses 2020; 12:v12050542. [PMID: 32423043 PMCID: PMC7290942 DOI: 10.3390/v12050542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/09/2020] [Accepted: 05/12/2020] [Indexed: 12/29/2022] Open
Abstract
Viruses are the most common cause of acute respiratory tract infections (ARTI). Human metapneumovirus (hMPV) frequently causes viral pneumonia which can become life-threatening if the virus spreads to the lungs. Even though hMPV was only isolated in 2001, this negative-stranded RNA virus has probably been circulating in the human population for many decades. Interestingly, almost all adults have serologic evidence of hMPV infection. A well-established host immune response is evoked when hMPV infection occurs. However, the virus has evolved to circumvent and even exploit the host immune response. Further, infection with hMPV induces a weak memory response, and re-infections during life are common. In this review, we provide a comprehensive overview of the different cell types involved in the immune response in order to better understand the immunopathology induced by hMPV. Such knowledge may contribute to the development of vaccines and therapeutics directed against hMPV.
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Affiliation(s)
- Marlies Ballegeer
- VIB-UGent Center for Medical Biotechnology, VIB, B-9052 Ghent, Belgium;
- Department of Biochemistry and Microbiology, Ghent University, B-9000 Ghent, Belgium
| | - Xavier Saelens
- VIB-UGent Center for Medical Biotechnology, VIB, B-9052 Ghent, Belgium;
- Department of Biochemistry and Microbiology, Ghent University, B-9000 Ghent, Belgium
- Correspondence:
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26
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Cell-Mediated Responses to Human Metapneumovirus Infection. Viruses 2020; 12:542. [PMID: 32423043 PMCID: PMC7290942 DOI: 10.3390/v12050542&set/a 882111696+808152660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Viruses are the most common cause of acute respiratory tract infections (ARTI). Human metapneumovirus (hMPV) frequently causes viral pneumonia which can become life-threatening if the virus spreads to the lungs. Even though hMPV was only isolated in 2001, this negative-stranded RNA virus has probably been circulating in the human population for many decades. Interestingly, almost all adults have serologic evidence of hMPV infection. A well-established host immune response is evoked when hMPV infection occurs. However, the virus has evolved to circumvent and even exploit the host immune response. Further, infection with hMPV induces a weak memory response, and re-infections during life are common. In this review, we provide a comprehensive overview of the different cell types involved in the immune response in order to better understand the immunopathology induced by hMPV. Such knowledge may contribute to the development of vaccines and therapeutics directed against hMPV.
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27
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Cell-Mediated Responses to Human Metapneumovirus Infection. Viruses 2020. [DOI: 10.3390/v12050542
expr 836379838 + 819716165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Viruses are the most common cause of acute respiratory tract infections (ARTI). Human metapneumovirus (hMPV) frequently causes viral pneumonia which can become life-threatening if the virus spreads to the lungs. Even though hMPV was only isolated in 2001, this negative-stranded RNA virus has probably been circulating in the human population for many decades. Interestingly, almost all adults have serologic evidence of hMPV infection. A well-established host immune response is evoked when hMPV infection occurs. However, the virus has evolved to circumvent and even exploit the host immune response. Further, infection with hMPV induces a weak memory response, and re-infections during life are common. In this review, we provide a comprehensive overview of the different cell types involved in the immune response in order to better understand the immunopathology induced by hMPV. Such knowledge may contribute to the development of vaccines and therapeutics directed against hMPV.
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28
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Alhazza IM, Ebaid H, Abdel-Salam B, Al-Tamimi JH, Hassan I, Rady AM, Mashaly AMA. Thymoquinone ameliorates Pachycondyla sennaarensis venom-induced acute toxic shock in male rats. BMC Pharmacol Toxicol 2019; 20:84. [PMID: 31847893 PMCID: PMC6918657 DOI: 10.1186/s40360-019-0375-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 11/26/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND For many decades, the sting of Samsun ant (Pachycondyla sennaarensis) has been a serious clinical challenge for the people living in some of the major Middle East and Asian countries. In the present study, the therapeutic potential of Nigella sativa derived plant extract component, thymoquinone (TQ) has been tested against the Samsun ant venom (SAV) at the toxic dose in the rats. METHODS The adult male rats were divided into four groups (n = 10): control, SAV treated, SAV + TQ treated and TQ alone treated. It was found that the sub-lethal dose of SAV alters not only many of the kidney and liver function markers but also induces oxidative stress in the animals. Moreover, the SAV also disturbs various immunological parameters including expression of PMNs, CD-80, CD-86, interleukins and other cytokines compromising the affected organism towards mild to severe allergic reactions including life-risking anaphylaxis. RESULTS The plant extract, TQ, effectively restores many of the biochemical and oxidative stress parameters comparable to the normal concomitant with improving the immunological aspects that might attributive in relieving from SAV-induced toxicity and allergic reactions in the affected organism to a greater extent. CONCLUSION Hence, TQ has an excellent antidote property against SAV-induced toxicities in vivo. Although the study is a vivid indication of the potential therapeutic potential of TQ against the SAV induced in vivo toxicity, yet the actual mechanism of interaction translating the toxicity amelioration warrants further investigations.
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Affiliation(s)
- Ibrahim M Alhazza
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Hossam Ebaid
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Bahaa Abdel-Salam
- Department of Biology, College of Science and Humanities in El-Quwiaya, 11961, Shaqra University, Shaqra, Saudi Arabia
| | - Jameel H Al-Tamimi
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Iftekhar Hassan
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.
| | - Ahmed M Rady
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Ashraf M A Mashaly
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
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29
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Ebaid H, Abdel-Salam B, Alhazza I, Al-Tamimi J, Hassan I, Rady A, Mashaly A, Mahmoud A, Sammour R. Samsum ant venom modulates the immune response and redox status at the acute toxic dose in vivo. J Venom Anim Toxins Incl Trop Dis 2019; 25:e20190020. [PMID: 31839800 PMCID: PMC6892565 DOI: 10.1590/1678-9199-jvatitd-2019-0020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 11/05/2019] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Ant venoms express surface molecules that participate in antigen presentation involving pro- and anti-inflammatory cytokines. This work aims to investigate the expression of MHC-II, CD80 and CD86 on the polymorphonuclear cells (PMNs) in rats injected with samsum ant venom (SAV). METHODS Rats were divided into three groups - control, SAV-treated (intraperitoneal route, 600 μg/kg), and SAV-treated (subcutaneous route, 600 μg/kg). After five doses, animals were euthanized and samples collected for analysis. RESULTS The subcutaneous SAV-trated rats presented decreased levels of glutathione with increased cholesterol and triglyceride levels. Intraperitoneal SAV-treated animals displayed significantly reduced concentrations of both IFN-γ and IL-17 in comparison with the control group. However, intraperitoneal and subcutaneous SAV-treated rats were able to upregulate the expressions of MHC-II, CD80 and CD86 on PMNs in comparison with the control respectively. The histological examination showed severe lymphocyte depletion in the splenic white pulp of the intraperitoneal SAV-injected rats. CONCLUSION Stimulation of PMNs by SAV leads to upregulation of MHC-II, CD 80, and CD 86, which plays critical roles in antigen presentation and consequently proliferation of T-cells. Subcutaneous route was more efficient than intraperitoneal by elevating MHC-II, CD80 and CD86 expression, disturbing oxidative stability and increasing lipogram concentration.
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Affiliation(s)
- Hossam Ebaid
- Department of Zoology, College of Science, King Saud University,
Riyadh 11451, Saudi Arabia
| | - Bahaa Abdel-Salam
- Department of Biology, College of Science and Humanities in
El-Quwiaya, 11961, Shaqra University, Saudi Arabia
| | - Ibrahim Alhazza
- Department of Zoology, College of Science, King Saud University,
Riyadh 11451, Saudi Arabia
| | - Jameel Al-Tamimi
- Department of Zoology, College of Science, King Saud University,
Riyadh 11451, Saudi Arabia
| | - Iftekhar Hassan
- Department of Zoology, College of Science, King Saud University,
Riyadh 11451, Saudi Arabia
| | - Ahmed Rady
- Department of Zoology, College of Science, King Saud University,
Riyadh 11451, Saudi Arabia
| | - Ashraf Mashaly
- Department of Zoology, College of Science, King Saud University,
Riyadh 11451, Saudi Arabia
| | - Ahmed Mahmoud
- Department of Zoology, College of Science, King Saud University,
Riyadh 11451, Saudi Arabia
| | - Reda Sammour
- Department of Zoology, College of Science, King Saud University,
Riyadh 11451, Saudi Arabia
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30
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Li Y, Wang W, Yang F, Xu Y, Feng C, Zhao Y. The regulatory roles of neutrophils in adaptive immunity. Cell Commun Signal 2019; 17:147. [PMID: 31727175 PMCID: PMC6854633 DOI: 10.1186/s12964-019-0471-y] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/25/2019] [Indexed: 12/16/2022] Open
Abstract
Neutrophils have long been considered as cells playing a crucial role in the immune defence against invading pathogens. Accumulating evidence strongly supported the direct and indirect regulatory effects of neutrophils on adaptive immunity. Exogenous cytokines or cytokines produced in an autocrine manner as well as a cell-to-cell contact between neutrophils and T cells could induce the expression of MHC-II and costimulatory molecules on neutrophils, supporting that neutrophils may function as antigen-presenting cells (APCs) in respects of presenting antigens and activating T cells. In addition to the inflammatory roles, neutrophils also have the propensity and ability to suppress the immune response through different mechanisms. In this review, we will mainly highlight the heterogeneity and functional plasticity of neutrophils and the antigen-presenting capacity of different neutrophil subsets. We also discuss mechanisms relevant to the regulatory effects of neutrophils on adaptive immunity. Understanding how neutrophils modulate adaptive immunity may provide novel strategies and new therapeutic approaches for diseases associated with neutrophils.
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Affiliation(s)
- Yang Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Fan Yang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China
| | - Chang Feng
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
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31
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Abstract
Neutrophils play a key role in innate immunity. As the dominant circulating phagocyte, they are rapidly recruited from the bloodstream to sites of infection or injury to internalize and destroy microbes. More recently, neutrophils have been identified in uninfected organs, challenging the classical view of their function. Here we show that neutrophils were present in lymph nodes (LNs) in homeostasis. Using flow cytometry and confocal imaging, we identified neutrophils within LNs in naive, unchallenged mice, including LNs draining the skin, lungs, and gastrointestinal tract. Neutrophils were enriched within specific anatomical regions, in the interfollicular zone, a site of T cell activation. Intravital two-photon microscopy demonstrated that LN neutrophils were motile, trafficked into LNs from both blood and tissues via high endothelial venules and afferent lymphatics, respectively, and formed interactions with dendritic cells in LNs. Murine and human LN neutrophils had a distinct phenotype compared with circulating neutrophils, with higher major histocompatibility complex II (MHCII) expression, suggesting a potential role in CD4 T cell activation. Upon ex vivo stimulation with IgG immune complex (IC), neutrophils up-regulated expression of MHCII and costimulatory molecules and increased T cell activation. In vivo, neutrophils were capable of delivering circulating IC to LNs, suggesting a broader functional remit. Overall, our data challenge the perception that neutrophil patrol is limited to the circulation in homeostasis, adding LNs to their routine surveillance territory.
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32
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Wang C, Fiering SN, Steinmetz NF. Cowpea Mosaic Virus Promotes Anti-Tumor Activity and Immune Memory in a Mouse Ovarian Tumor Model. ADVANCED THERAPEUTICS 2019; 2:1900003. [PMID: 33969181 PMCID: PMC8101952 DOI: 10.1002/adtp.201900003] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Indexed: 01/08/2023]
Abstract
Cowpea mosaic virus (CPMV) is a promising platform nanotechnology with applications as a cancer therapeutic. To understand the therapeutic potential of CPMV in more detail, its antitumor mechanisms are investigated using a syngeneic immunocompetent murine orthotopic ovarian cancer model (ID8-Defb29/Vegf-A). CPMV treatment in situ promotes tumor regression and prevents tumor recurrence. Although CPMV does not kill tumor cells directly, it promotes an intra-tumoral cytokine response which induces pre-existing myeloid cells to break immunotolerance and initiate antitumor responses. The upregulation of interleukin-6 and interferon-γ as well as the downregulation of IL-10 and transforming growth factor β are observed, associated with activation and repolarization of tumor-associated macrophages and neutrophils to an anti-tumor phenotype. Furthermore, the in situ administration of CPMV recruits dendritic cells and natural killer cells to the tumor site, and induces the expression of costimulatory molecules on CD11b- myeloid cells. By converting immunosuppressive myeloid cells into potent antigen-presenting cells, in situ CPMV treatment significantly improves effector and memory CD4+ and CD8+ T cell responses and promoted systemic tumor-specific cytotoxic CD8+ T cell activity. CPMV in situ immunotherapy induces significant tumor control in an aggressive ovarian tumor model by coordinating innate and adaptive immune responses involving neutrophils, macrophages, and T cells.
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Affiliation(s)
- Chao Wang
- Department of NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Steven N Fiering
- Department of Microbiology and Immunology and Norris Cotton Cancer Center, Dartmouth University, Lebanon, NH 03756, USA
| | - Nicole F Steinmetz
- Department of NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA
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33
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Castro-Dopico T, Clatworthy MR. IgG and Fcγ Receptors in Intestinal Immunity and Inflammation. Front Immunol 2019; 10:805. [PMID: 31031776 PMCID: PMC6473071 DOI: 10.3389/fimmu.2019.00805] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 03/26/2019] [Indexed: 12/15/2022] Open
Abstract
Fcγ receptors (FcγR) are cell surface glycoproteins that mediate cellular effector functions of immunoglobulin G (IgG) antibodies. Genetic variation in FcγR genes can influence susceptibility to a variety of antibody-mediated autoimmune and inflammatory disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). More recently, however, genetic studies have implicated altered FcγR signaling in the pathogenesis of inflammatory bowel disease (IBD), a condition classically associated with dysregulated innate and T cell immunity. Specifically, a variant of the activating receptor, FcγRIIA, with low affinity for IgG, confers protection against the development of ulcerative colitis, a subset of IBD, leading to a re-evaluation of the role of IgG and FcγRs in gastrointestinal tract immunity, an organ system traditionally associated with IgA. In this review, we summarize our current understanding of IgG and FcγR function at this unique host-environment interface, from the pathogenesis of colitis and defense against enteropathogens, its contribution to maternal-fetal cross-talk and susceptibility to cancer. Finally, we discuss the therapeutic implications of this information, both in terms of how FcγR signaling pathways may be targeted for the treatment of IBD and how FcγR engagement may influence the efficacy of therapeutic monoclonal antibodies in IBD.
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Affiliation(s)
- Tomas Castro-Dopico
- Molecular Immunity Unit, MRC Laboratory of Molecular Biology, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Menna R. Clatworthy
- Molecular Immunity Unit, MRC Laboratory of Molecular Biology, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
- NIHR Cambridge Biomedical Research CentreCambridge, United Kingdom
- Cellular Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
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34
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Jackson DG. Leucocyte Trafficking via the Lymphatic Vasculature- Mechanisms and Consequences. Front Immunol 2019; 10:471. [PMID: 30923528 PMCID: PMC6426755 DOI: 10.3389/fimmu.2019.00471] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 02/21/2019] [Indexed: 01/15/2023] Open
Abstract
The lymphatics fulfill a vital physiological function as the conduits through which leucocytes traffic between the tissues and draining lymph nodes for the initiation and modulation of immune responses. However, until recently many of the molecular mechanisms controlling such migration have been unclear. As a result of careful research, it is now apparent that the process is regulated at multiple stages from initial leucocyte entry and intraluminal crawling in peripheral tissue lymphatics, through to leucocyte exit in draining lymph nodes where the migrating cells either participate in immune responses or return to the circulation via efferent lymph. Furthermore, it is increasingly evident that most if not all leucocyte populations migrate in lymph and that such migration is not only important for immune modulation, but also for the timely repair and resolution of tissue inflammation. In this article, I review the latest research findings in these areas, arising from new insights into the distinctive ultrastructure of lymphatic capillaries and lymph node sinuses. Accordingly, I highlight the emerging importance of the leucocyte glycocalyx and its novel interactions with the endothelial receptor LYVE-1, the intricacies of endothelial chemokine secretion and sequestration that direct leucocyte trafficking and the significance of the process for normal immune function and pathology.
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Affiliation(s)
- David G Jackson
- MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
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35
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Orchestration of Adaptive T Cell Responses by Neutrophil Granule Contents. Mediators Inflamm 2019; 2019:8968943. [PMID: 30983883 PMCID: PMC6431490 DOI: 10.1155/2019/8968943] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/28/2019] [Accepted: 02/06/2019] [Indexed: 01/05/2023] Open
Abstract
Neutrophils are the most abundant leukocytes in peripheral blood and respond rapidly to danger, infiltrating tissues within minutes of infectious or sterile injury. Neutrophils were long thought of as simple killers, but now we recognise them as responsive cells able to adapt to inflammation and orchestrate subsequent events with some sophistication. Here, we discuss how these rapid responders release mediators which influence later adaptive T cell immunity through influences on DC priming and directly on the T cells themselves. We consider how the release of granule contents by neutrophils—through NETosis or degranulation—is one way in which the innate immune system directs the phenotype of the adaptive immune response.
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36
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Castell SD, Harman MF, Morón G, Maletto BA, Pistoresi-Palencia MC. Neutrophils Which Migrate to Lymph Nodes Modulate CD4 + T Cell Response by a PD-L1 Dependent Mechanism. Front Immunol 2019; 10:105. [PMID: 30761151 PMCID: PMC6362305 DOI: 10.3389/fimmu.2019.00105] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 01/14/2019] [Indexed: 01/20/2023] Open
Abstract
It is well known that neutrophils are rapidly recruited to a site of injury or infection and perform a critical role in pathogen clearance and inflammation. However, they are also able to interact with and regulate innate and adaptive immune cells and some stimuli induce the migration of neutrophils to lymph nodes (LNs). Previously, we demonstrated that the immune complex (IC) generated by injecting OVA into the footpad of OVA/CFA immunized mice induced the migration of OVA+ neutrophils to draining LNs (dLNs). Here we investigate the effects of these neutrophils which reach dLNs on CD4+ T cell response. Our findings here strongly support a dual role for neutrophils in dLNs regarding CD4+ T cell response modulation. On the one hand, the CD4+ T cell population expands after the influx of OVA+ neutrophils to dLNs. These CD4+ T cells enlarge their proliferative response, activation markers and IL-17 and IFN-γ cytokine production. On the other hand, these neutrophils also restrict CD4+ T cell expansion. The neutrophils in the dLNs upregulate PD-L1 molecules and are capable of suppressing CD4+ T cell proliferation. These results indicate that neutrophils migration to dLNs have an important role in the homeostasis of adaptive immunity. This report describes for the first time that the influx of neutrophils to dLNs dependent on IC presence improves CD4+ T cell response, at the same time controlling CD4+ T cell proliferation through a PD-L1 dependent mechanism.
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Affiliation(s)
- Sofía D Castell
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología, Córdoba, Argentina
| | - María F Harman
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología, Córdoba, Argentina
| | - Gabriel Morón
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología, Córdoba, Argentina
| | - Belkys A Maletto
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología, Córdoba, Argentina
| | - María C Pistoresi-Palencia
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología, Córdoba, Argentina
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37
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Breslin JW, Yang Y, Scallan JP, Sweat RS, Adderley SP, Murfee WL. Lymphatic Vessel Network Structure and Physiology. Compr Physiol 2018; 9:207-299. [PMID: 30549020 PMCID: PMC6459625 DOI: 10.1002/cphy.c180015] [Citation(s) in RCA: 210] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease. © 2019 American Physiological Society. Compr Physiol 9:207-299, 2019.
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Affiliation(s)
- Jerome W. Breslin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Ying Yang
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Joshua P. Scallan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Richard S. Sweat
- Department of Biomedical Engineering, Tulane University, New Orleans, LA
| | - Shaquria P. Adderley
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - W. Lee Murfee
- Department of Biomedical Engineering, University of Florida, Gainesville, FL
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38
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Woodberry T, Bouffler SE, Wilson AS, Buckland RL, Brüstle A. The Emerging Role of Neutrophil Granulocytes in Multiple Sclerosis. J Clin Med 2018; 7:E511. [PMID: 30513926 PMCID: PMC6306801 DOI: 10.3390/jcm7120511] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 11/26/2018] [Accepted: 11/29/2018] [Indexed: 12/11/2022] Open
Abstract
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong autoimmune, neurodegenerative, and neuroinflammatory component. Most of the common disease modifying treatments (DMTs) for MS modulate the immune response targeting disease associated T and B cells and while none directly target neutrophils, several DMTs do impact their abundance or function. The role of neutrophils in MS remains unknown and research is ongoing to better understand the phenotype, function, and contribution of neutrophils to both disease onset and stage of disease. Here we summarize the current state of knowledge of neutrophils and their function in MS, including in the rodent based MS model, and we discuss the potential effects of current treatments on these functions. We propose that neutrophils are likely to participate in MS pathogenesis and their abundance and function warrant monitoring in MS.
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Affiliation(s)
- Tonia Woodberry
- The John Curtin School of Medical Research, The Australian National University, Canberra 2600, Australia.
| | - Sophie E Bouffler
- The John Curtin School of Medical Research, The Australian National University, Canberra 2600, Australia.
| | - Alicia S Wilson
- The John Curtin School of Medical Research, The Australian National University, Canberra 2600, Australia.
| | - Rebecca L Buckland
- The John Curtin School of Medical Research, The Australian National University, Canberra 2600, Australia.
| | - Anne Brüstle
- The John Curtin School of Medical Research, The Australian National University, Canberra 2600, Australia.
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39
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Clarke F, Purvis HA, Sanchez-Blanco C, Gutiérrez-Martinez E, Cornish GH, Zamoyska R, Guermonprez P, Cope AP. The protein tyrosine phosphatase PTPN22 negatively regulates presentation of immune complex derived antigens. Sci Rep 2018; 8:12692. [PMID: 30139951 PMCID: PMC6107551 DOI: 10.1038/s41598-018-31179-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 08/06/2018] [Indexed: 12/11/2022] Open
Abstract
A C1858T single nucleotide polymorphism within PTPN22 (which encodes PTPN22R620W) is associated with an enhanced susceptibility to multiple autoimmune diseases including type 1 diabetes and rheumatoid arthritis. Many of the associated autoimmune diseases have an autoantibody component to their pathology. Fc receptors (FcRs) recognise autoantibodies when they bind to autoantigens and form immune complexes. After immune complex binding and receptor crosslinking, FcRs signal via Src and Syk family kinases, leading to antigen uptake, presentation and cytokine secretion. Ptpn22 encodes a protein tyrosine phosphatase that negatively regulates Src and Syk family kinases proximal to immunoreceptor signalling cascades. We therefore hypothesised that PTPN22 regulates immune complex stimulated FcR responses in dendritic cells (DCs). Bone marrow derived DCs (BMDCs) from wild type (WT) or Ptpn22-/- mice were pulsed with ovalbumin:anti-ovalbumin immune complexes (ova ICs). Co-culture with WT OT-II T cells revealed that ova IC pulsed Ptpn22-/- BMDCs have an enhanced capability to induce T cell proliferation. This was associated with an increased capability of Ptpn22-/- BMDCs to present immune complex derived antigens and to form ova IC dependent DC-T cell conjugates. These findings highlight PTPN22 as a regulator of FcR mediated responses and provide a link between the association of PTPN22R620W with autoantibody associated autoimmune diseases.
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Affiliation(s)
- Fiona Clarke
- Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 1UL, United Kingdom.
| | - Harriet A Purvis
- Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 1UL, United Kingdom
| | - Cristina Sanchez-Blanco
- Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 1UL, United Kingdom
| | - Enrique Gutiérrez-Martinez
- Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 1UL, United Kingdom
| | - Georgina H Cornish
- Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 1UL, United Kingdom
| | - Rose Zamoyska
- Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, EH9 3FL, United Kingdom
| | - Pierre Guermonprez
- Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 1UL, United Kingdom
| | - Andrew P Cope
- Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 1UL, United Kingdom
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40
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Liang F, Lindgren G, Sandgren KJ, Thompson EA, Francica JR, Seubert A, De Gregorio E, Barnett S, O'Hagan DT, Sullivan NJ, Koup RA, Seder RA, Loré K. Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake. Sci Transl Med 2018; 9:9/393/eaal2094. [PMID: 28592561 DOI: 10.1126/scitranslmed.aal2094] [Citation(s) in RCA: 162] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 04/14/2017] [Indexed: 12/21/2022]
Abstract
The innate immune mechanisms by which adjuvants enhance the potency and protection of vaccine-induced adaptive immunity are largely unknown. We introduce a model to delineate the steps of how adjuvant-driven innate immune activation leads to priming of vaccine responses using rhesus macaques. Fluorescently labeled HIV-1 envelope glycoprotein (Env) was administered together with the conventional aluminum salt (alum) adjuvant. This was compared to Env given with alum with preabsorbed Toll-like receptor 7 (TLR7) ligand (alum-TLR7) or the emulsion MF59 because they show superiority over alum for qualitatively and quantitatively improved vaccine responses. All adjuvants induced rapid and robust immune cell infiltration to the injection site in the muscle. This resulted in substantial uptake of Env by neutrophils, monocytes, and myeloid and plasmacytoid dendritic cells (DCs) and migration exclusively to the vaccine-draining lymph nodes (LNs). Although less proficient than monocytes and DCs, neutrophils were capable of presenting Env to memory CD4+ T cells. MF59 and alum-TLR7 showed more pronounced cell activation and overall higher numbers of Env+ cells compared to alum. This resulted in priming of higher numbers of Env-specific CD4+ T cells in the vaccine-draining LNs, which directly correlated with increased T follicular helper cell differentiation and germinal center formation. Thus, strong innate immune activation promoting efficient vaccine antigen delivery to infiltrating antigen-presenting cells in draining LNs is an important mechanism by which superior adjuvants enhance vaccine responses.
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Affiliation(s)
- Frank Liang
- Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Gustaf Lindgren
- Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Kerrie J Sandgren
- Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Elizabeth A Thompson
- Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Joseph R Francica
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | | | | | | | | | - Nancy J Sullivan
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Richard A Koup
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Robert A Seder
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Karin Loré
- Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. .,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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41
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Whittaker Hawkins RF, Patenaude A, Dumas A, Jain R, Tesfagiorgis Y, Kerfoot S, Matsui T, Gunzer M, Poubelle PE, Larochelle C, Pelletier M, Vallières L. ICAM1+ neutrophils promote chronic inflammation via ASPRV1 in B cell-dependent autoimmune encephalomyelitis. JCI Insight 2017; 2:96882. [PMID: 29212956 DOI: 10.1172/jci.insight.96882] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 10/23/2017] [Indexed: 12/16/2022] Open
Abstract
Neutrophils contribute to demyelinating autoimmune diseases, yet their phenotype and functions have been elusive to date. Here, we demonstrate that ICAM1 surface expression distinguishes extra- from intravascular neutrophils in the mouse CNS during experimental autoimmune encephalomyelitis (EAE). Transcriptomic analysis of these 2 subpopulations indicated that neutrophils, once extravasated, acquire macrophage-like properties, including the potential for immunostimulation and MHC class II-mediated antigen presentation. In corroboration, super-resolution (3D stimulated emission-depletion [STED]) microscopy revealed neutrophils forming synapses with T and B cells in situ. Further, neutrophils specifically express the aspartic retroviral-like protease ASPRV1, which increases in the CNS during EAE and severe cases of multiple sclerosis. Without ASPRV1, mice immunized with a new B cell-dependent myelin antigen (but not with the traditional myelin oligodendrocyte glycoprotein peptide) develop a chronic phase of EAE that is less severe and even completely fades in many individuals. Therefore, ICAM1+ macrophage-like neutrophils can play both shared and nonredundant roles in autoimmune demyelination, among them perpetuating inflammation via ASPRV1.
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Affiliation(s)
- Ryder F Whittaker Hawkins
- Neuroscience Unit, University Hospital Center of Quebec - Laval University, Quebec City, Quebec, Canada
| | - Alexandre Patenaude
- Neuroscience Unit, University Hospital Center of Quebec - Laval University, Quebec City, Quebec, Canada
| | - Aline Dumas
- Neuroscience Unit, University Hospital Center of Quebec - Laval University, Quebec City, Quebec, Canada
| | - Rajiv Jain
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Yodit Tesfagiorgis
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Steven Kerfoot
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Takeshi Matsui
- Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany
| | - Patrice E Poubelle
- Infectious and Immune Disease Unit, University Hospital Center of Quebec - Laval University, Quebec City, Quebec, Canada
| | - Catherine Larochelle
- Neuroimmunology Research Laboratory, University of Montreal Hospital Research Center, Montreal, Quebec, Canada
| | - Martin Pelletier
- Infectious and Immune Disease Unit, University Hospital Center of Quebec - Laval University, Quebec City, Quebec, Canada
| | - Luc Vallières
- Neuroscience Unit, University Hospital Center of Quebec - Laval University, Quebec City, Quebec, Canada
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42
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Döring Y, Megens R, Soehnlein O, Drechsler M. Neutrophilic granulocytes – promiscuous accelerators of atherosclerosis. Thromb Haemost 2017; 106:839-48. [DOI: 10.1160/th11-07-0501] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 09/28/2011] [Indexed: 12/23/2022]
Abstract
SummaryNeutrophils, as part of the innate immune system, are classically described to be main actors during the onset of inflammation enforcing rapid neutralisation and clearance of pathogens. Besides their wellstudied role in acute inflammatory processes, recent advances strongly indicate a so far underappreciated importance of neutrophils in initiation and development of atherosclerosis. This review focuses on current findings on the role of neutrophils in atherosclerosis. As pro-inflammatory mechanisms of neutrophils have primarily been studied in the microvascular environment; we here aim at translating these into the context of macrovascular inflammation in atherosclerosis. Since much of the pro-inflammatory activities of neutrophils stem from instructing neighbouring cell types, we highlight the promiscuous interplay between neutrophils and platelets, monocytes, T lymphocytes, and dendritic cells and its possible relevance to atherosclerosis.
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43
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Grant ML, Shields N, Neumann S, Kramer K, Bonato A, Jackson C, Baird MA, Young SL. Combining dendritic cells and B cells for presentation of oxidised tumour antigens to CD8 + T cells. Clin Transl Immunology 2017; 6:e149. [PMID: 28791124 PMCID: PMC5539416 DOI: 10.1038/cti.2017.28] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 12/30/2022] Open
Abstract
The dendritic cell (DC) is the foremost antigen-presenting cell (APC) for ex vivo expansion of tumour-specific patient T cells. Despite marked responses in some patients following reinfusion of DC-activated autologous or HLA-matched donor T cells, overall response rates remain modest in solid tumours. Furthermore, most studies aim to generate immune responses against defined tumour-associated antigens (TAA), however, meta-analysis reveals that those approaches have less clinical success than those using whole tumour cells or their components. Tumour lysate (TL) is used as a source of tumour antigen in clinical trials and potentially represents the full range of TAAs in an undefined state. Little is known about how different APCs cooperate to present TL antigens. We examined the effect of oxidised whole-cell lysate (ox-L) versus soluble fraction freeze-thaw lysate (s-L) on bone marrow-derived DCs and macrophages, and magnetic bead-isolated splenic B cells. The APCs were used individually, or in combination, to prime T cells. CD8+ T cells produced interferon (IFN)-γ in response to both s-L and ox-L, but only proliferated in response to ox-L. IFN-γ production and proliferation was enhanced by priming with the DC+B cell combination. Compared to DC alone, a trend toward greater interleukin (IL)-12 production was observed when DC+B cell were loaded with s-L and ox-L antigens. CD8+ T-cell specific lysis in vivo was greatest in ox-L-primed groups and DC+B cell priming significantly increased in vivo cytotoxicity compared to DC alone. These improved T-cell responses with two APCs and stressed cell lysate has implications for APC-based adoptive cell therapies.
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Affiliation(s)
- Melanie L Grant
- Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Nicholas Shields
- Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Silke Neumann
- Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Katrin Kramer
- Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Andrea Bonato
- Ambulatorio Veterinario Summano, Via Europa, Santorso, Italy
| | | | - Margaret A Baird
- Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Sarah L Young
- Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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44
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Cheemarla NR, Baños-Lara MDR, Naidu S, Guerrero-Plata A. Neutrophils regulate the lung inflammatory response via γδ T cell infiltration in an experimental mouse model of human metapneumovirus infection. J Leukoc Biol 2017; 101:1383-1392. [PMID: 28336678 DOI: 10.1189/jlb.4a1216-519rr] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 03/01/2017] [Accepted: 03/03/2017] [Indexed: 12/28/2022] Open
Abstract
Neutrophils are the most abundant leukocytes in human circulation. They are the first immune cell population recruited to the sites of infection. However, the role of neutrophils to regulate host immune responses during respiratory viral infections is largely unknown. To elucidate the role of neutrophils in respiratory antiviral defense, we used an experimental mouse model of human metapneumovirus (HMPV) infection. HMPV, a member of the Paramyxoviridae family, is a leading respiratory pathogen causing severe symptoms, such as bronchiolitis and pneumonia, in young, elderly, and immunocompromised patients. We demonstrate that neutrophils are the predominant population of immune cells recruited into the lungs after HMPV infection. This led us to hypothesize that neutrophils represent a key player of the immune response during HMPV infection, thereby regulating HMPV-induced lung pathogenesis. Specific depletion of neutrophils in vivo using a mAb and simultaneous infection with HMPV exhibited higher levels of inflammatory cytokines, pulmonary inflammation, and severe clinical disease compared with HMPV-infected, competent mice. Interestingly, the lack of neutrophils altered γδ T cell accumulation in the lung. The absence of γδ T cells during HMPV infection led to reduced pulmonary inflammation. These novel findings demonstrate that neutrophils play a critical role in controlling HMPV-induced inflammatory responses by regulating γδ T cell infiltration to the site of infection.
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Affiliation(s)
- Nagarjuna R Cheemarla
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA; and
| | - Ma Del Rocío Baños-Lara
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA; and
| | - Shan Naidu
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA; and
| | - Antonieta Guerrero-Plata
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA; and .,Center for Experimental Infectious Disease Research, Louisiana State University, Baton Rouge, Louisiana, USA
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45
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Casserly CS, Nantes JC, Whittaker Hawkins RF, Vallières L. Neutrophil perversion in demyelinating autoimmune diseases: Mechanisms to medicine. Autoimmun Rev 2017; 16:294-307. [PMID: 28161558 DOI: 10.1016/j.autrev.2017.01.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
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46
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Howard LM, Hoek KL, Goll JB, Samir P, Galassie A, Allos TM, Niu X, Gordy LE, Creech CB, Prasad N, Jensen TL, Hill H, Levy SE, Joyce S, Link AJ, Edwards KM. Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial. PLoS One 2017; 12:e0167488. [PMID: 28099485 PMCID: PMC5242433 DOI: 10.1371/journal.pone.0167488] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 11/15/2016] [Indexed: 12/28/2022] Open
Abstract
Background Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. Objective and Methods We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18–49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. Results Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination. Conclusions Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. Trial Registration ClinicalTrials.gov NCT01573312
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Affiliation(s)
- Leigh M. Howard
- Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Kristen L. Hoek
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | | | - Parimal Samir
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Allison Galassie
- Department of Chemistry, Vanderbilt University, Nashville, TN, United States of America
| | - Tara M. Allos
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Xinnan Niu
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Laura E. Gordy
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - C. Buddy Creech
- Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Nripesh Prasad
- HudsonAlpha Institute for Biotechnology; Huntsville, AL, United States of America
| | | | - Heather Hill
- The Emmes Corporation, Rockville, MD, United States of America
| | - Shawn E. Levy
- HudsonAlpha Institute for Biotechnology; Huntsville, AL, United States of America
| | - Sebastian Joyce
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
- Veterans Administration Tennessee Valley Healthcare System, Nashville, TN, United States of America
| | - Andrew J. Link
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
- * E-mail: (KME); (AJL)
| | - Kathryn M. Edwards
- Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, United States of America
- * E-mail: (KME); (AJL)
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47
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Sin YW, Newman C, Dugdale HL, Buesching C, Mannarelli ME, Annavi G, Burke T, Macdonald DW. No Compensatory Relationship between the Innate and Adaptive Immune System in Wild-Living European Badgers. PLoS One 2016; 11:e0163773. [PMID: 27695089 PMCID: PMC5047587 DOI: 10.1371/journal.pone.0163773] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 09/14/2016] [Indexed: 11/19/2022] Open
Abstract
The innate immune system provides the primary vertebrate defence system against pathogen invasion, but it is energetically costly and can have immune pathological effects. A previous study in sticklebacks found that intermediate major histocompatibility complex (MHC) diversity correlated with a lower leukocyte coping capacity (LCC), compared to individuals with fewer, or many, MHC alleles. The organization of the MHC genes in mammals, however, differs to the highly duplicated MHC genes in sticklebacks by having far fewer loci. Using European badgers (Meles meles), we therefore investigated whether innate immune activity, estimated functionally as the ability of an individual’s leukocytes to produce a respiratory burst, was influenced by MHC diversity. We also investigated whether LCC was influenced by factors such as age-class, sex, body condition, season, year, neutrophil and lymphocyte counts, and intensity of infection with five different pathogens. We found that LCC was not associated with specific MHC haplotypes, MHC alleles, or MHC diversity, indicating that the innate immune system did not compensate for the adaptive immune system even when there were susceptible MHC alleles/haplotypes, or when the MHC diversity was low. We also identified a seasonal and annual variation of LCC. This temporal variation of innate immunity was potentially due to physiological trade-offs or temporal variation in pathogen infections. The innate immunity, estimated as LCC, does not compensate for MHC diversity suggests that the immune system may function differently between vertebrates with different MHC organizations, with implications for the evolution of immune systems in different taxa.
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Affiliation(s)
- Yung Wa Sin
- Wildlife Conservation Research Unit, Department of Zoology, University of Oxford, Recanati-Kaplan Centre, Tubney House, Abingdon Road, Tubney, Abingdon, Oxfordshire, OX13 5QL, United Kingdom
- NERC Biomolecular Analysis Facility, Department of Animal and Plant Sciences, University of Sheffield, Sheffield, S10 2TN, United Kingdom
- Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Harvard University, 26 Oxford Street, Cambridge, MA, 02138, United States of America
- * E-mail:
| | - Chris Newman
- Wildlife Conservation Research Unit, Department of Zoology, University of Oxford, Recanati-Kaplan Centre, Tubney House, Abingdon Road, Tubney, Abingdon, Oxfordshire, OX13 5QL, United Kingdom
| | - Hannah L. Dugdale
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, PO Box 11103, 9700 CC, Groningen, Netherlands
- School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Christina Buesching
- Wildlife Conservation Research Unit, Department of Zoology, University of Oxford, Recanati-Kaplan Centre, Tubney House, Abingdon Road, Tubney, Abingdon, Oxfordshire, OX13 5QL, United Kingdom
| | - Maria-Elena Mannarelli
- NERC Biomolecular Analysis Facility, Department of Animal and Plant Sciences, University of Sheffield, Sheffield, S10 2TN, United Kingdom
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk, NR4 7TJ, United Kingdom
| | - Geetha Annavi
- Wildlife Conservation Research Unit, Department of Zoology, University of Oxford, Recanati-Kaplan Centre, Tubney House, Abingdon Road, Tubney, Abingdon, Oxfordshire, OX13 5QL, United Kingdom
- Faculty of Science, Department of Biology, University of Putra Malaysia, UPM 43400, Serdang, Selangor, Malaysia
| | - Terry Burke
- NERC Biomolecular Analysis Facility, Department of Animal and Plant Sciences, University of Sheffield, Sheffield, S10 2TN, United Kingdom
| | - David W. Macdonald
- Wildlife Conservation Research Unit, Department of Zoology, University of Oxford, Recanati-Kaplan Centre, Tubney House, Abingdon Road, Tubney, Abingdon, Oxfordshire, OX13 5QL, United Kingdom
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Kelher MR, Banerjee A, Gamboni F, Anderson C, Silliman CC. Antibodies to major histocompatibility complex class II antigens directly prime neutrophils and cause acute lung injury in a two-event in vivo rat model. Transfusion 2016; 56:3004-3011. [PMID: 27667662 DOI: 10.1111/trf.13817] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 07/18/2016] [Accepted: 07/26/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND Transfusion-related acute lung injury (TRALI) is a significant cause of mortality, especially after transfusions containing antibodies to major histocompatibility complex (MHC) class II antigens. We hypothesize that a first event induces both 1) polymorphonuclear neutrophils (PMNs) to express MHC class II antigens, and 2) activation of the pulmonary endothelium, leading to PMN sequestration, so that the infusion of specific MHC class II antibodies to these antigens causes PMN-mediated acute lung injury (ALI). STUDY DESIGN AND METHODS Rats were treated with saline (NS), endotoxin (lipopolysaccharide [LPS]), or cytokines (interferon-γ [IFNγ], macrophage colony-stimulating factor [MCSF], tumor necrosis factor-α [TNFα]); the PMNs were isolated; and the surface expression of the MHC class II antigen OX6 and priming by OX6 antibodies were measured by flow cytometry or priming assays. RESULTS A two-event model of ALI was completed with NS, LPS, or IFNγ/MCSF/TNFα (first events) and the infusion of OX6 (second event). Compared with NS incubation, rats treated with either LPS or IFNγ/MCSF/TNFα exhibited OX6 PMN surface expression, OX6 antibodies primed the formyl-methionyl-leucyl phenylalanine (fMLF)-activated respiratory burst, and PMN sequestration was increased. OX6 antibody infusion into LPS-incubated or IFNγ/MCSF/TNFα-incubated rats elicited ALI, the OX6 antibody was present on the PMNs, and PMN depletion abrogated ALI. CONCLUSION Proinflammatory first events induce PMN MHC class II surface expression, activation of the pulmonary endothelium, and PMN sequestration such that the infusion of cognate antibodies precipitates TRALI.
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Affiliation(s)
- Marguerite R Kelher
- Research Laboratory, Bonfils Blood Center, Denver, Colorado.,Department of Surgery, University of Colorado Denver, Aurora, Colorado
| | - Anirban Banerjee
- Department of Surgery, University of Colorado Denver, Aurora, Colorado
| | - Fabia Gamboni
- Department of Surgery, University of Colorado Denver, Aurora, Colorado
| | - Cameron Anderson
- Department of Surgery, University of Colorado Denver, Aurora, Colorado
| | - Christopher C Silliman
- Research Laboratory, Bonfils Blood Center, Denver, Colorado.,Department of Surgery, University of Colorado Denver, Aurora, Colorado.,Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, Colorado
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Aquaporin-9-expressing neutrophils are required for the establishment of contact hypersensitivity. Sci Rep 2015; 5:15319. [PMID: 26489517 PMCID: PMC4614820 DOI: 10.1038/srep15319] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 09/21/2015] [Indexed: 01/01/2023] Open
Abstract
Aquaporin-9 (AQP9), a water/glycerol channel protein, is expressed in several immune cells including neutrophils; however, its role in immune response remains unknown. Here we show the involvement of AQP9 in hapten-induced contact hypersensitivity (CHS), as a murine model of skin allergic contact dermatitis, using AQP9 knockout (AQP9−/−) mice. First, the CHS response to hapten dinitrofluorobenzene (DNFB) was impaired in AQP9−/− mice compared with wild-type (WT) mice. Adoptive transfer of sensitized AQP9−/− draining lymph node (dLN) cells into WT recipients resulted in a reduced CHS response, indicating impaired sensitization in AQP9−/− mice. Second, administration of WT neutrophils into AQP9−/− mice during sensitization rescued the impaired CHS response. Neutrophil recruitment to dLNs upon hapten application was attenuated by AQP9 deficiency. Coincidentally, AQP9−/− neutrophils showed a reduced CC-chemokine receptor 7 (CCR7) ligand-induced migration efficacy, which was attributed to the attenuated recruitment of neutrophils to dLNs. Furthermore, we found that neutrophil deficiency, observed in AQP9−/− or neutrophil-depleted mice, decreased IL-17A production by dLN cells, which might be responsible for T cell activation during a subsequent CHS response. Taken together, these findings suggest that AQP9 is required for the development of sensitization during cutaneous acquired immune responses via regulating neutrophil function.
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Up-regulation of programmed cell death 1 ligand 1 on neutrophils may be involved in sepsis-induced immunosuppression: an animal study and a prospective case-control study. Anesthesiology 2015; 122:852-63. [PMID: 25437496 DOI: 10.1097/aln.0000000000000525] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Recent studies have shown that neutrophils may display an antigen-presenting function and inhibit lymphocyte proliferation by expressing programmed cell death 1 ligand 1 (PD-L1). The current study was performed to investigate the effect of neutrophils and their pathophysiological significance during sepsis. METHODS Neutrophil PD-L1 expression was determined in both septic mice (n = 6) and patients (n = 41). Neutrophils from septic mice were subtyped into PD-L1 and PD-L1 populations to determine their phenotypes and functions. Septic neutrophils were cocultured with lymphocytes to observe the effect of septic neutrophils on lymphocyte apoptosis. RESULTS The PD-L1 level on neutrophils from septic mice was significantly up-regulated (21.41 ± 4.76%). This level increased with the progression of sepsis and the migration of neutrophils from the bone marrow to the blood and peritoneal cavity. The percentages of CD11a, CD62L, and C-C chemokine receptor type 2 were lower, whereas the percentages of CD16 and CD64 were higher on PD-L1 neutrophils than on PD-L1 neutrophils. The migratory capacity of PD-L1 neutrophils was compromised. Septic neutrophils induced lymphocyte apoptosis via a contact mechanism, and this process could be reversed by anti-PD-L1 antibody. PD-L1 was also up-regulated on neutrophils from patients with severe sepsis (14.6% [3.75%, 42.1%]). The levels were negatively correlated with the monocyte human leukocyte antigen-DR level and positively correlated with the severity of septic patients. Neutrophil PD-L1 was a predictor for the prognosis of severe sepsis, with an area of 0.74 under the receiver operating curve. CONCLUSIONS PD-L1 is up-regulated on neutrophils during sepsis, which may be related to sepsis-induced immunosuppression.
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