Platelet-derived extracellular vesicles (pEVs) are nanoscale, membrane-bound vesicles released by platelets during activation or apoptosis. They contain various bioactive and non-bioactive molecules and play significant roles in numerous physiological and pathological processes through intercellular communication, thus attracting growing attention in biomedical research.

This review comprehensively overviews the biogenesis, clearance, and molecular characteristics of pEVs. It also covers current methodologies for their isolation and characterization. The therapeutic implications of pEVs in key clinical settings like tissue regeneration, hemostasis, immune modulation, and vascular repair, with a focus on cancer progression, wound healing, and hemorrhagic shock management, are explored. Their role in cellular signal transduction is examined, and their functional properties are compared with other platelet-derived products such as platelet-rich plasma.

pEVs show potential as both therapeutic agents and diagnostic biomarkers. They are involved in modulating inflammatory responses, promoting angiogenesis, and enhancing cellular repair mechanisms.

Future research should concentrate on optimizing their therapeutic efficacy, refining biomarker applications, and exploring targeted delivery strategies to fully utilize their potential in regenerative medicine, oncology, and hemostasis management.

The relationship between the environment and diseases is a crucial and complex topic that has garnered significant attention in recent years. In our study, we also follow the thread and explore the correlation between microplastics (MPs) and osteoporosis (OP).

We found that MPs were detected in the blood samples of nearly all participants. Moreover, It was compelling that PVC and PET emerged as the most common MP polymers in our study. A verification process was conducted comparing the clinical data with the results of MPs detection. This analysis revealed a significant exposure risk to MPs from sources such as bottled water, take-out containers. Through molecular biology techniques, we confirmed that MPs have a significant toxic effect on osteoblasts and associated with abnormal gene expression.

MPs may be considered to have a potential correlation with the progression of OP.

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasome-dependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

Cell death occurs continuously throughout individual development. By removing damaged or senescent cells, cell death not only facilitates morphogenesis during the developmental process, but also contributes to maintaining homeostasis after birth. In addition, cell death reduces the spread of pathogens by eliminating infected cells. Cell death is categorized into two main forms: necrosis and programmed cell death. Programmed cell death encompasses several types, including autophagy, pyroptosis, apoptosis, necroptosis, ferroptosis, and PANoptosis. Autophagy, a mechanism of cell death that maintains cellular equilibrium via the breakdown and reutilization of proteins and organelles, is implicated in regulating almost all forms of cell death in pathological contexts. Notably, necroptosis, ferroptosis, and PANoptosis are directly classified as autophagy-mediated cell death. Therefore, regulating autophagy presents a therapeutic approach for treating diseases such as inflammation and tumors that arise from abnormalities in other forms of programmed cell death. This review focuses on the crosstalk between autophagy and other programmed cell death modalities, providing new perspectives for clinical interventions in inflammatory and neoplastic diseases.

Developing oral drug delivery systems is promising for ulcerative colitis (UC). However, the key challenges, including formulation degradation under harsh gastric conditions, poor targeting efficiency, and limited colonic residence, lead to poor therapeutic efficacy that still needs to be tackled. Effective treatment requires a safe, efficacious, enzyme- and pH-responsive, biomucoadhesive oral drug delivery system to overcome these challenges. Therefore, we have developed chitosan-armored 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) nanoliposomes amalgamated with synthesized beta-sitosterol-sinapic acid (Be-S) conjugate, further encapsulated with 3,4-methylenedioxy-β-nitrostyrene (MNS) as NLRP3 inhibitor, termed C@MN@DMBe-S, to overcome the limitation of free MNS and sinapic acid. Formulated by the thin-film hydration method and processed through extrusion, these unilamellar liposomes demonstrated structural stability and mucoadhesive properties due to chitosan coating. This configuration protected the nanoliposomes from the gastric acidic environment and allowed retention in the inflamed colon for 48 h. The enzyme-responsive C@MN@DMBe-S nanoliposome releases sinapic acid at the inflamed colonic site via esterase activity, providing sustained and controlled release of MNS. This synergistic action delivers antioxidant and anti-inflammatory effects while influencing the gut microbiota composition by releasing short-chain fatty acids. Moreover, therapeutic investigations revealed that C@MN@DMBe-S exhibited superior efficacy compared with free MNS when administered orally. The formulation effectively downregulated NF-κB, NLRP3, Caspase-1, and IL-1β expression while upregulating MUC5AC expression, indicating enhanced anti-inflammatory and protective effects and thereby promoting mucosal healing. In addition, C@MN@DMBe-S was found to regulate immune cell expression and effectively downregulate neutrophil infiltration. This armor- and enzyme-responsive strategy elucidates the impact of oral nanomedicines on mitigating UC and is demonstrated as an effective treatment.

Drug-induced toxicity is an important issue in clinical medicine, which typically results in organ dysfunction and adverse health consequences. The family of NOD-like receptors (NLRs) includes intracellular proteins involved in recognizing pathogens and triggering innate immune responses, including the activation of the NLRP3 inflammasome. The NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3) inflammasome is a critical component for both innate and adaptive immune responses and has been implicated in various drug-induced toxicities, including hepatic, renal, and cardiovascular diseases. The unusual activation of the NLRP3 inflammasome causes the release of pro-inflammatory cytokines, such as IL-1β and IL-18, which can lead to more damage to tissues. Targeting NLRP3 inflammasome is a potential therapeutic endeavour for suppressing drug-induced toxicity. This review provides insights into the mechanism, drug-induced organ toxicity, therapeutic strategies, and prospective therapeutic approaches of the NLRP3 inflammasome and summarizes the developing therapies that target the inflammasome unit. This review has taken up one of the foremost endeavours in understanding and inhibiting the NLRP3 inflammasome as a means of generating safer pharmacological therapies.

Bacterial lung infections cause severe host responses. Here, we showed that global deficiency of caspase-1 can protect against lethal pulmonary Escherichia coli infection by reducing the necroptosis of infiltrated neutrophils, which are key players in immune responses in the lung. Mechanistically, neutrophil necroptosis was not directly triggered in a cell-intrinsic manner by invading bacteria but was triggered by bacteria-stimulated pyroptotic epithelial cell supernatants in vitro. In validation experiments, chimeric mice with nonhematopoietic caspase-1 or GSDMD knockout were protected from lung E. coli infection and exhibited decreased neutrophil death. Nonhematopoietic pyroptosis facilitates the release of dsRNAs and contributes to neutrophil ZBP1-related necroptosis. Moreover, blocking dsRNA or depleting ZBP1 ameliorated the pathophysiological process of pulmonary E. coli infection. Overall, our results demonstrate a paradigm of communication between necroptosis and pyroptosis in different cell types in cooperation with microbes and hosts and suggest that therapeutic targeting of the pyroptosis or necroptosis pathway may prevent pulmonary bacterial infection.

Parkinson's disease (PD), the second most common neurodegenerative disease with notable clinical heterogeneity, has Parkinson disease dementia (PDD) that severely impacts patients' quality of life. As no effective treatment exists, this study aimed to find potential drug targets for PD cognitive disorders.

Two-sample Mendelian randomization (MR) and transcriptome analysis were used to identify PD biomarkers. Protein-protein interaction (PPI), gene ontology (GO), and KEGG pathway analyses explored biological effects. A nomogram model was developed.

76 Mendelian randomization genes (MRGs) from MR and 1771 differentially expressed genes (DEGs) from the transcriptome were obtained. Three significant shared DEGs (S-DEGs) were identified, with USP8 and STXBP6 having strong diagnostic value for PDD. The nomogram model with these two genes showed enhanced predictive ability. These genes had physical interactions, co-localization, and correlated with ODC and NEU immune cells. USP8 was linked to five diseases, and STXBP6 to one.

USP8, STXBP6, and immune cells (ODC and NEU) associated with PDD were identified, offering new insights into PD progression.

Hypothyroidism is associated with anxiety and depression. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown. This study aimed to investigate the role of the NLRP1 inflammasome in anxiety-like behavior in mice with hypothyroidism. Male C57BL/6j mice were divided into three groups: euthyroid controls, a hypothyroid model group induced by propylthiouracil, and a hypothyroid group treated with levothyroxine (L-T4). Anxiety-like behavior was assessed using both the open field test and the elevated plus maze. Protein levels of NLRP1 inflammasome components and associated cytokines in the hippocampus were examined by Western blot analysis. Mice with hypothyroidism exhibited anxiety-like behavior, as evidenced by decreased activity in the central area of the open field and reduced time spent in the open arms of the elevated plus maze. These behavioral changes were accompanied by an increased expression of NLRP1 inflammasome components (NLRP1, ASC, and Caspase-1) and associated cytokines (IL-1β, IL-18, and IL-6) in the hippocampus. L-T4 treatment reversed both the behavioral deficits and inflammatory changes. Our findings highlight the crucial role of NLRP1 inflammasome activation in the hippocampus in mediating anxiety-like behavior in hypothyroid mice, shedding light on the mechanisms underlying hypothyroidism-related psychiatric comorbidities and identifying potential therapeutic targets.

Systemic autoinflammatory diseases are rare conditions resulting from dysregulation of the innate immune system, culminating in repetitive bouts of systemic inflammation without the presence of external or self-antigens. Most systemic autoinflammatory diseases are associated with mutations in genes affecting the innate immune response. Tumor necrosis factor is a central player in the pathogenesis of numerous chronic inflammatory disorders, and anti-tumor necrosis factor therapy is widely used in the clinical management of systemic autoinflammatory diseases. Tumor necrosis factor inhibitors block the interaction of tumor necrosis factor with its 2 receptors, tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2. These inhibitors primarily target soluble tumor necrosis factor, which mainly binds to tumor necrosis factor receptor 1, exerting anti-inflammatory effects. Interestingly, tumor necrosis factor inhibitors also affect transmembrane tumor necrosis factor, which engages tumor necrosis factor receptor 2 to initiate reverse signaling. This reverse signaling can activate innate immune cells, prevent apoptosis, or paradoxically inhibit the production of pro-inflammatory cytokines. Tumor necrosis factor inhibitors also promote the release of soluble tumor necrosis factor receptor 2, which neutralizes circulating tumor necrosis factor. Some agents targeting tumor necrosis factor receptor 2 can even act as agonists, triggering reverse signaling by binding to transmembrane tumor necrosis factor. While effective, prolonged use of tumor necrosis factor inhibitors may cause significant side effects due to the widespread expression and pleiotropic functions of tumor necrosis factor receptors. A more thorough understanding of the mechanisms underlying the action of tumor necrosis factor inhibitors is required to develop a more effective and safer treatment for systemic autoinflammatory diseases. This article reviews current studies on the role of the innate immune system in systemic autoinflammatory disease pathogenesis, the impact of anti-tumor necrosis factor therapy on innate immune cells, and perspectives on developing improved agents targeting tumor necrosis factor or its receptors.

Neutrophilic dermatoses are defined as inflammatory skin diseases characterized by sterile infiltration of polymorphonuclear neutrophils into various cutaneous layers. Although, in many cases, neutrophilic dermatoses represent the cutaneous counterpart of autoinflammatory diseases, this is not always the case, and there are other causes associated with this group of diseases, such as the administration of certain drugs or an underlying tumor. However, understanding the autoinflammatory context in which most of these entities develop, as well as their close relationship with autoimmunity, is key to comprehending their pathogenesis. In addition, understanding the mechanisms by which neutrophils migrate to the dermis and become activated is fundamental for interpreting the morphological findings of these biopsies. Finally, the description of a new group of neutrophilic dermatoses in recent years, in relation to keratinization disorders, has been crucial for understanding the best therapeutic approach for these difficult-to-manage entities.

This study clarifies the interaction between autophagy and inflammasome within the cancer framework. The inflammasome generates pro-inflammatory cytokines to direct the immune response to pathogens and cellular stressors. Autophagy maintains cellular homeostasis and can either promote or inhibit cancer. These pathways interact to affect tumorigenesis, immune responses, and therapy. Autophagy controls inflammasome activity by affecting cancer pathogenesis and tumor microenvironment inflammation, highlighting novel cancer therapeutic approaches. Recent studies indicate that modulating autophagy and inflammasome pathways can boost anti-cancer immunity, reduce drug-resistance, and improve therapeutic efficacy. Recent studies indicate modulating inflammasome and autophagy pathways can augment anti-cancer immunity, mitigate therapy resistance, and improve treatment efficacy. Cancer research relies on understanding the inflammasome-autophagy relationship to develop targeted therapies that enhance anti-tumor efficacy and reduce inflammatory symptoms. Customized therapies may improve outcomes based on autophagy gene variations and inflammasome polymorphisms. This study investigates autophagy pathways and the inflammasome in tumor immunopathogenesis, cytokine function, and cancer therapeutic strategies, highlighting their significance in cancer biology and treatment.

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is pivotal in orchestrating the immune response induced by nanoparticle adjuvants. Understanding the intricate mechanisms underlying the activation of NLRP3 inflammasome by these adjuvants is crucial for deciphering their immunomodulatory properties. This review explores the involvement of the NLRP3 inflammasome in mediating immune responses triggered by nanoparticle adjuvants. It delves into the signaling pathways and cellular mechanisms involved in NLRP3 activation, highlighting its significance in modulating the efficacy and safety of nanoparticle-based adjuvants. A comprehensive grasp of the interplay between NLRP3 inflammasome and nanoparticle adjuvants holds promise for optimizing vaccine design and advancing immunotherapeutic strategies.

Eurotium cristatum (EC), the dominant fungus in Fuzhuan brick tea, has significant applications in food fermentation and pharmaceutical industries, exhibiting probiotic properties, but further investigation of its intestinal benefits is required. This study characterized the EC-520 strain through whole genome sequencing and evaluated its effects on rat colons using histomorphology, 16S rRNA sequencing, and untargeted metabolomics. The genomic analysis revealed that EC-520 possessed a 28.37 Mb genome distantly related to Aspergillus flavus. The 16S results demonstrated that EC-520 significantly increased the abundance of Bacteroidota (p < 0.05) while decreasing the Proteobacteria and Firmicutes/Bacteroidota ratio (the F/B ratio); at the genus level, it elevated Muribaculaceae and Clostridia_UCG-014 while reducing harmful bacteria. The metabolomic results showed that EC-520 also significantly altered tryptamine, caproic acid, isocaproic acid, and erucic acid (p < 0.05). Additionally, the Spearman's correlation analysis revealed that Muribaculaceae_unclassified and Clostridia_UCG-014_unclassified were significantly positively correlated with tryptamine, caproic acid, isocaproic acid, and erucic acid. Therefore, this study suggested that EC-520 enhanced the colon barrier and increased the abundance of Muribaculaceae_unclassified and Clostridia_UCG-014_unclassified, thus promoting the secretion of tryptamine and affecting the release of 5-hydroxytryptamine (5-HT). It also promoted the secretion of certain fatty acids, enhancing the balance of the colonic microbiota. This study provides a new view for a comprehensive understanding of EC's regulatory role in the colon.

Emerging evidence indicates that a baseline level of controlled innate immune signaling is required to support proper brain function. However, little is known about the function of most innate immune pathways in homeostatic neurobiology. Here, we report a role for astrocyte-dependent inflammasome signaling in regulating hippocampal plasticity. Inflammasomes are multiprotein complexes that promote caspase-1-mediated interleukin (IL)-1 and IL-18 production in response to pathogens and tissue damage. We observed that inflammasome complex formation was regularly detected under homeostasis in hippocampal astrocytes and that its assembly is dynamically regulated in response to learning and regional activity. Conditional ablation of caspase-1 in astrocytes limited hyperexcitability in an acute seizure model and impacted hippocampal plasticity via modulation of synaptic protein density, neuronal activity, and perineuronal net coverage. Caspase-1 and IL-18 regulated hippocampal IL-33 production and related plasticity. These findings reveal a homeostatic function for astrocyte inflammasome activity in regulating hippocampal physiology in health and disease.

The regeneration of the enthesis remains a formidable challenge in regenerative medicine. However, key regulators underlying unsatisfactory regeneration remain poorly understood. This study reveals that the purinergic receptor P2X7 (P2X7R)/Nod-like receptor family protein 3 (NLRP3) inflammasome axis suppresses enthesis regeneration by amplifying IL-1β-mediated inflammatory cross-talk and suppressing docosatrienoic acid (DTA) metabolic cross-talk. NLRP3 inflammasomes were activated in macrophages following enthesis injury, thereby impairing the histological and functional recovery of the injured enthesis. Single-cell RNA sequencing (scRNA-seq) indicated that Nlrp3 knockout attenuated pathological inflammation and ameliorated the detrimental effects of IL-1β signaling cross-talk. Furthermore, NLRP3 inflammasomes suppressed the secretion of anti-inflammatory cytokines (IL-10 and IL-13) and DTA. The NLRP3 inflammasome-mediated secretome reduced differentiation and migration of stem cells. Neutralizing IL-1β or replenishing docosatrienoic acid accelerated enthesis regeneration. Moreover, conditional knockout of P2rx7 in myeloid cells attenuated NLRP3 inflammasome activation and facilitated enthesis regeneration. This study demonstrates that the P2X7R/NLRP3 inflammasome axis represents a promising therapeutic target for enthesis repair.

Obesity, a worldwide health emergency, is defined by excessive fat accumulation and significantly impacts metabolic health. In addition to its recognized association with cardiovascular disease, diabetes, and other metabolic illnesses, recent studies have revealed the connection between obesity and neurodegeneration. The main reason for this link is inflammation caused by the growth of fat tissue, which activates harmful processes that affect how the brain works. Fat tissue, particularly the fat around the organs, produces various substances that cause inflammation, such as cytokines (TNF-α, IL-6), adipokines (leptin, resistin), and free fatty acids. These chemicals cause low-grade, persistent systemic inflammation, which is becoming more widely acknowledged as a major factor in peripheral metabolic dysfunction and pathology of the central nervous system (CNS). Inflammatory signals in the brain cause neuroinflammatory reactions that harm neuronal structures, change neuroplasticity, and disrupt synaptic function. When obesity-related inflammation is present, the brain's resident immune cells, known as microglia, become hyperactivated, which can lead to the production of neurotoxic chemicals, which can cause neuronal death. This neuroinflammation exacerbates the negative effects of obesity on brain health and is linked to cognitive decline, Alzheimer's disease, and other neurodegenerative disorders. Moreover, the blood-brain barrier (BBB) exhibits increased permeability during inflammatory states, facilitating the infiltration of peripheral immune cells and cytokines into the brain, hence exacerbating neurodegeneration. Adipose tissue is a source of chronic inflammatory mediators, which are examined in this review along with the molecular pathways that connect inflammation brought on by obesity to neurodegeneration. Additionally, it addresses various anti-inflammatory treatment approaches, including lifestyle modifications, anti-inflammatory medications, and gut microbiota modulation, to lessen the metabolic and neurological effects of obesity. Recognizing the link between obesity and inflammation opens up new opportunities for early intervention and the development of targeted treatments to prevent or alleviate neurodegenerative disorders.

Liver fibrosis is a critical precursor to the progression of cirrhosis and liver cancer. However, the development of precision therapies for this condition has been impeded by incompletely elucidated molecular mechanisms. Activin receptor like kinase 5 (ALK5), termed TGF-β type I receptor (TGF-βRI), has been identified as a promising therapeutic target for antifibrotic drug development. In this study, we designed and synthesized two novel thiazole derivatives (J-1155 and J-1156) featuring enantiomeric amino acid moieties to selectively target ALK5 for hepatic fibrosis treatment. Our data demonstrated that both compounds effectively attenuate hepatic fibrosis and associated inflammation through dual inhibition of the TGF-β/Smad signaling pathway and blockade of the P2X7R-NLRP3 inflammasome axis. In comparison, J-1156 demonstrated superior overall therapeutic efficacy to J-1155 in terms of anti-fibrotic efficacy, while J-1155 exhibited superior modulation of Smurf2. Collectively, our observations demonstrate the potential of J-1155 and J-1156 as dual novel therapeutic agents targeting hepatic fibrosis.

Inflammasomes are multiprotein complexes of the innate immune system that sense different pathogens or danger signals, and have been implicated in the pathogenesis of multiple human inflammatory diseases. The translocation of adaptor protein ASC from the nucleus to the cytosol is important for inflammasome assembly and activation, but the mechanism remains unclear. Here we show that pharmacological inhibition or genetic deletion of chromosome region maintenance 1 (CRM1) in macrophages significantly inhibits the activation of NLRP3, AIM2, NLRC4 and pyrin inflammasomes. Mechanistically, CRM1 directly binds to the PYD domain of ASC to promote its nuclear-cytosolic transport. More importantly, treatment with CRM1 inhibitor KPT-330 or deletion of CRM1 in myeloid cells attenuates the pathological symptoms of experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our findings reveal that CRM1 is an essential mediator for ASC nuclear export to promote inflammasome assembly and activation, which provides a potential target for inflammasome-related diseases.

Non-lymphoid immunoregulatory cells, including mesenchymal stem cells (MSCs), myeloid-derived suppressor cells (MDSCs), regulatory macrophages (Mregs), and tolerogenic dendritic cells (Tol-DCs), play critical roles in maintaining immune homeostasis. However, their therapeutic application in autoimmune diseases and graft-versus-host disease (GVHD) has received comparatively less attention. Induced pluripotent stem cells (iPSCs) offer a promising platform for cell engineering, enabling superior quality control, scalable production, and large-scale in vitro expansion of iPSC-derived non-lymphoid immunoregulatory cells. These advances pave the way for their broader application in autoimmune disease and GVHD therapy. Recent innovations in iPSC differentiation protocols have facilitated the generation of these cell types with functional characteristics akin to their primary counterparts. This review explores the unique features and generation processes of iPSC-derived non-lymphoid immunoregulatory cells, their therapeutic potential in GVHD and autoimmune disease, and their progress toward clinical translation. It emphasizes the phenotypic and functional diversity within each cell type and their distinct effects on disease modulation. Despite these advancements, challenges persist in optimizing differentiation efficiency, ensuring functional stability, and bridging the gap to clinical application. By synthesizing current methodologies, preclinical findings, and translational efforts, this review underscores the transformative potential of iPSC-derived non-lymphoid immunoregulatory cells in advancing cell-based therapies for alloimmune and autoimmune diseases.

There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

Nanoparticles, defined by their nanoscale dimensions and unique physicochemical properties, are widely utilized in healthcare, electronics, environmental sciences, and consumer products. However, increasing evidence of their potential embryotoxic effects during pregnancy underscores the need for a molecular-level understanding of their interactions during embryonic development. Nanoparticles such as titanium dioxide, silver, cerium oxide, copper oxide, and quantum dots can cross the placental barrier and interfere with crucial developmental processes. At the molecular level, they disrupt signaling pathways like Wnt and Hedgehog, induce oxidative stress and inflammation, and cause genotoxic effects, all critical during sensitive phases, such as organogenesis. Furthermore, these nanoparticles interact directly with cellular components, including DNA, proteins, and lipids, impairing cellular function and viability. Innovative strategies to mitigate nanoparticle toxicity, such as surface modifications and incorporation of biocompatible coatings, are discussed as potential solutions to reduce adverse molecular interactions. Various laboratory animal models used to investigate nanoparticle-induced embryotoxicity are evaluated for their efficacy and limitations, providing insights into their applicability for understanding these effects. This Account examines the molecular mechanisms by which nanoparticles compromise embryonic development and emphasizes the importance of designing safer nanoparticles to minimize maternal-fetal exposure risks, particularly in biomedical applications.

Upon introduction into biological environments, nanoparticles undergo the spontaneous formation of a dynamic protein corona, which continually evolves and significantly modifies their physicochemical properties and interactions with biological systems. This evolving protein corona can critically impact the nanoparticles' endocytic pathways and targeting efficiency, potentially altering their functional characteristics and obscuring their intended therapeutic effects. Despite considerable focus on the characterization of corona proteins and their impact on nanoparticle uptake, the intracellular processes and their effects on immunogenicity are not yet thoroughly understood. Supramolecular polymer nanoparticles (SNPs) with a highly hydrophobic core are recognized for triggering NLRP3 inflammasome activation, a key component of the innate immune system. Here, it is reported that the protein corona formation on SNPs exerts an inhibitory effect on the activation pathway of NLRP3 inflammasome. The protein corona impairs the intrinsic capacity of SNPs to induce lysosomal membrane rupture, thereby diminishing the cellular stress signals necessary for the formation of the NLRP3 inflammasome complex. Furthermore, the cells transport SNPs with an attached protein corona to recycling endosomes, where they are sorted and prepared for exocytosis. Conversely, nascent SNPs are primarily confined to late endosomes and lysosomes, leading to lysosomal rupture and inflammasome activation. This differential routing reflects the significant impact of the protein corona on the cellular handling and subsequent biological activity of nanoparticles. In summary, this study elucidates the fundamental role of the protein corona in shaping the intracellular disposition of nanoparticles, with implications for modulating their interactions with the immune system.

SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood. In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58). Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC. Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.

Intricate interactions between immune cells and cytokines define psoriasis, a chronic inflammatory skin condition that is immunological-mediated. Cytokines, including interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), chemokines, and transforming growth factor-β (TGF-β), are essential for controlling cellular activity and immunological responses, maintaining homeostasis and contributing to the pathogenesis of psoriasis. These molecules modulate the immune microenvironment by either promoting or suppressing inflammation, which significantly impacts therapeutic outcomes. Recent research indicates that treatment strategies targeting cytokines and chemokines have significant potential, offering new approaches for regulating the immune system, inhibiting the progression of psoriasis, and reducing adverse effects of traditional therapies. This review consolidates current knowledge on cytokine and chemokine signaling pathways in psoriasis and examines their significance in treatment. Specific attention is given to cytokines like IL-17, IL-23, and TNF-α, underscoring the necessity for innovative therapies to modulate these pathways and address inflammatory processes. This review emphasizes the principal part of cytokines in the -pathological process of psoriasis and explores the challenges and opportunities they present for therapeutic intervention. Furthermore, we examine recent advancements in targeted therapies, with a particular focus on monoclonal antibodies, in ongoing research and clinical trials.

Long-term exposure to arsenic, a prevalent environmental contaminant, has been implicated in the pathogenesis of various hepatic conditions. Hepatic stellate cells (HSCs) are central to the development of liver fibrosis. Recently, the involvement of interleukin-17 (IL-17) and the NOD-like receptor protein 3 (NLRP3) inflammasome in hepatic pathologies has attracted significant research interest. Hepatocyte pyroptosis, a form of programmed cell death, is a critical factor in the occurrence of inflammation. The objective of this study was to investigate the specific roles of IL-17 and NLRP3 in the arsenic-induced activation of HSCs through hepatocyte pyroptosis. We pretreated MIHA cells with MCC950 (1 and 5 μM) and secukinumab (10 and 100 nM) for 4 h, then with NaAsO2 (25 μM) for 24 h at 37 °C under 5% CO2. After incubation, the cell-culture supernatant was collected and mixed with serum-free high-glucose DMEM medium in a 1:1 ratio to prepare the conditioned medium, which was subsequently used for the culture of LX-2 cells. The results showed that exposure to NaAsO2 induced hepatocellular pyroptosis, which led to the release of the inflammatory cytokines IL-18 and IL-1β and subsequent activation of HSCs. Treatment with the inhibitors MCC950 and secukinumab significantly reduced the secretion of Extracellular matrix (ECM) components and attenuated HSC activation. These results demonstrate that blocking the IL-17 and NLRP3 signaling pathways significantly reduces HSC activation and attenuates hepatic fibrogenesis. These results provide novel molecular targets for the prevention and treatment of arsenic-related liver fibrosis.

The complement system expressed intracellularly and known as complosome has been indicated as a trigger in the regulation of lymphocyte functioning. The expression of its genes was confirmed also in several types of human bone marrow-derived stem cells: mononuclear cells (MNCs), very small embryonic-like stem cells (VSELs), hematopoietic stem/progenitor cells (HSPCs), endothelial progenitors (EPCs) and mesenchymal stem cells (MSCs). In our previous studies, we demonstrated the expression of complosome proteins including C3, C5, C3aR, and cathepsin L in purified HSPCs. However, there is still a lack of results showing the expression of complosome system elements and other immunity-related proteins in human HSPCs at the level of single cell resolution.

We employed scRNA-seq to investigate comprehensively the expression of genes connected with immunity, in two populations of human HSPCs: CD34+Lin-CD45+ and CD133+Lin-CD45+, with the division to subpopulations. We focused on genes coding complosome elements, selected cytokines, and genes related to antigen presentation as well as related to immune regulation.

We observed the differences in the expression of several genes e.g. C3AR1 and C5AR1 between two populations of HSPCs: CD34+LinCD45+ and CD133+Lin-CD45+ resulting from their heterogeneous nature. However, in both kinds of HSPCs, we observed similar cell subpopulations expressing genes (e.g. NLRP3 and IL-1β) at the same level, which suggests the presence of cells performing similar functions connected with the activation of inflammatory processes contributing to the body's defense against infections.

To our best knowledge, it is the first time that expression of complosome elements was studied in HSPCs at the single cell resolution with the use of single cell sequencing. Thus, our data sheds new light on complosome as a novel regulator of hematopoiesis that involves intracrine activation of the C5a-C5aR-Nlrp3 inflammasome axis.

Neuropsychiatric disorders significantly impact global health and socioeconomic well-being, highlighting the urgent need for effective treatments. Chronic inflammation, often driven by the innate immune system, is a key feature of many neuropsychiatric conditions. NOD-like receptors (NLRs), which are intracellular sensors, detect danger signals and trigger inflammation. Among these, NLR protein (NLRP) inflammasomes play a crucial role by releasing pro-inflammatory cytokines and inducing a particular cell death process known as pyroptosis. Pyroptosis is defined as a proinflammatory form of programmed cell death executed by cysteine-aspartic proteases, also known as caspases. Currently, the role of pyroptotic flux has emerged as a critical factor in innate immunity and the pathogenesis of multiple diseases. Emerging evidence suggests that the induction of pyroptosis, primarily due to NLRP inflammasome activation, is involved in the pathophysiology of various neuropsychiatric disorders, including depression, stress-related issues, schizophrenia, autism spectrum disorders, and neurodegenerative diseases. Within this framework, the current review explores the complex relationship between pyroptosis and neuropsychiatric diseases, aiming to identify potential therapeutic targets for these challenging conditions.

P2X7 purinergic receptor (P2X7R) is a promising target for the development of new anti-inflammatory therapies. This can be inferred from the number of pharmaceutical patents aimed at inhibitors of this receptor and the number of clinical trials related to P2X7 in progress. A previous study demonstrated that α-cyanocinnamylboronic acid derivatives can be valuable starting points for designing P2X7 inhibitors. Encouraged by previous results, new 2-cyanocinamic boronic acids were prepared and evaluated for their cytotoxicity, ability to inhibit human and mouse P2X7 receptors, and anti-inflammatory effects in vitro and in vivo in ATP-induced mouse paw edema. In the present work, a series of 2-cyanocinamic boronic acids were evaluated for their effects on the function and intracellular signaling of the purinergic receptor P2X7. Additionally, the anti-inflammatory properties of the series were investigated through in vitro and in vivo experiments. The selectivity and affinity for inhibiting the P2X7 receptor were investigated in U937 cells via in silico assays. We observed that 3 l inhibited P2X7 receptor function and intracellular signaling in vitro and inflammation in vivo after binding to P2X7 receptor allosteric sites.

Cardiopulmonary bypass in tetralogy of Fallot (TOF) corrective surgery induces hyperinflammation by activating NLRP3, caspase-1, and interleukin-ιβ (IL-ιβ), subsequently triggering an interleukin-10 (IL-10) response. Despite its known metabolic and anti-inflammatory effects, the impact of the modified Atkins diet (MAD) in pediatric cardiac surgery remains unexplored, with no studies on its use in TOF patients undergoing open-heart surgery. The aim of this study was to assess the effect of MAD on the expression of NLRP3, caspase-1, IL-ιβ, and IL-10, in TOF patients undergoing open-heart surgery. A double-arm, randomized-controlled trial was conducted with 44 TOF patients. The treatment group (n = 22) received the MAD, a low-carbohydrate, high-fat regimen with unrestricted fat and protein intake for at least 14 days preoperatively, while the control group (n = 22) followed a standard diet without carbohydrate restriction. Blood plasma and infundibulum heart tissues were collected for analysis. Whole blood samples were collected using a winged infusion needle before the intervention, an Abbocath infusion needle after 14 days of intervention, and a syringe without a needle connected to an arterial line in patients undergoing open-heart surgery at 6, 24, and 48  hours post-surgical correction. Infundibulum heart tissues were collected during the open-heart surgery. This study demonstrated significant differences in NLRP3 protein expression (p = 0.015), caspase-1 protein expression (p = 0.001), and IL-10 levels between after intervention and 6-, 24-, and 48-hours post-surgery in the MAD group compared to the control group. In contrast, no significant differences in IL-10 levels were observed in the control group between after intervention and 48  hours post-surgery (p = 0.654). In conclusion, MAD may modulate perioperative inflammation in TOF patients undergoing open-heart surgery by downregulating NLRP3 and caspase-1 expression while sustaining IL-10 levels. Despite reduced NLRP3 and caspase-1 expression, unchanged IL-ιβ levels indicate alternative regulatory mechanisms.

JOURNAL/nrgr/04.03/01300535-202504000-00030/figure1/v/2024-07-06T104127Z/r/image-tiff Our previous studies have reported that activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to restore the neuroinflammatory response, along with myelin and synaptic structural alterations in the prefrontal cortex, and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice. Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles, the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue, which inhibited the activation of the NLRP3 inflammasome, was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., pyrin domain-containing 1, caspase recruitment domain-containing 4, and absent in melanoma 2, as well as the alterations in inflammatory genes (interleukin-1β, interleukin-18, inducible nitric oxide synthase, nuclear factor-kappa B, monocyte chemoattractant protein-1, and C-X3-C motif chemokine ligand 1) and miRNAs (miR-21a-5p, miR-146a-5p, and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

Brain death (BD) and cold storage (CS) are critical factors that induce inflammation in donor kidneys, compromising organ quality. We investigated whether treating kidneys from BD rats with an inflammasome Nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor (MCC950) followed by CS could reduce kidney inflammation.

BD rats were assigned to MCC950-treated or nontreated (NT) groups. Kidneys were evaluated immediately before CS (T0) and after 12 h (T12) and 24 h (T24) of CS. Mean arterial pressure, serum creatinine, gene/protein expression, and histology were evaluated.

At T0, MCC950 treatment did not affect mean arterial pressure but tended to reduce serum creatinine and ameliorated the histological score of acute tubular necrosis. However, MCC950 reduced NLRP3 , caspase-1 , interleukin (IL)-1β , IL-6 , Kim-1 , nuclear factor kappa B , tumor necrosis factor alpha , and caspase-3 gene expression while increasing IL-10 cytokine gene expression. After 12 h of CS, only the expression of the NLRP3 and caspase-1 genes decreased, and after 24 h of CS, no further changes in the gene expression profile were observed. The levels of the inflammasome proteins NLRP3, caspase-1, and IL-1β consistently decreased across all time points (T0, T12, and T24).

These findings suggest that MCC950 treatment holds promise for mitigating the proinflammatory state observed in kidneys after BD and CS.

Erectile dysfunction (ED) is a prevalent condition affecting male sexual health, characterized by the inability to achieve or maintain satisfactory erections. ED has a multifactorial pathogenesis in which psychological, hormonal, neurologic, cardiovascular, and lifestyle factors all contribute to a progressive decline of erectile function. A critical underlying mechanism involves oxidative stress (OS), an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, which disrupts endothelial function, reduces nitric oxide (NO) bioavailability, and contributes to vascular dysfunction. This narrative review explores the interplay between OS and ED, focusing on the roles of ROS sources such as NADPH oxidase, xanthine oxidase, uncoupled nitric oxide synthase, and mitochondrial dysfunction. It examines the impact of OS on chronic conditions like hypertension, diabetes mellitus, hyperlipidemia, hypogonadism, and lifestyle factors like smoking and obesity, which exacerbate ED through endothelial and systemic effects. Emerging research underscores the potential of antioxidant therapies and lifestyle interventions to restore redox balance, improve endothelial function, and mitigate ED's progression. This review also highlights gaps in understanding the molecular pathways linking ROS to ED, emphasizing the need for further research to develop targeted therapeutic strategies.

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens.

Ubiquitin ligases play pivotal roles in the regulation of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a critical process in innate immunity and inflammatory responses. This review explores the intricate mechanisms by which various E3 ubiquitin ligases exert both positive and negative influences on NLRP3 inflammasome activity through diverse post-translational modifications. Negative regulation of NLRP3 inflammasome assembly is mediated by several E3 ligases, including F-box and leucine-rich repeat protein 2 (FBXL2), tripartite motif-containing protein 31 (TRIM31), and Casitas B-lineage lymphoma b (Cbl-b), which induce K48-linked ubiquitination of NLRP3, targeting it for proteasomal degradation. Membrane-associated RING-CH 7 (MARCH7) similarly promotes K48-linked ubiquitination leading to autophagic degradation, while RING finger protein (RNF125) induces K63-linked ubiquitination to modulate NLRP3 function. Ariadne homolog 2 (ARIH2) targets the nucleotide-binding domain (NBD) domain of NLRP3, inhibiting its activation, and tripartite motif-containing protein (TRIM65) employs dual K48 and K63-linked ubiquitination to suppress inflammasome assembly. Conversely, Pellino2 exemplifies a positive regulator, promoting NLRP3 inflammasome activation through K63-linked ubiquitination. Additionally, ubiquitin ligases influence other components critical for inflammasome function. TNF receptor-associated factor 3 (TRAF3) mediates K63 polyubiquitination of apoptosis-associated speck-like protein containing a CARD (ASC), facilitating its degradation, while E3 ligases regulate caspase-1 activation and DEAH-box helicase 33 (DHX33)-NLRP3 complex formation through specific ubiquitination events. Beyond direct inflammasome regulation, ubiquitin ligases impact broader innate immune signaling pathways, modulating pattern-recognition receptor responses and dendritic cell maturation. Furthermore, they intricately control NOD1/NOD2 signaling through K63-linked polyubiquitination of receptor-interacting protein 2 (RIP2), crucial for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) activation. Furthermore, we explore how various pathogens, including bacteria, viruses, and parasites, have evolved sophisticated strategies to hijack the host ubiquitination machinery, manipulating NLRP3 inflammasome activation to evade immune responses. This comprehensive analysis provides insights into the molecular mechanisms underlying inflammasome regulation and their implications for inflammatory diseases, offering potential avenues for therapeutic interventions targeting the NLRP3 inflammasome. In conclusion, ubiquitin ligases emerge as key regulators of NLRP3 inflammasome activation, exhibiting a complex array of functions that finely tune immune responses. Understanding these regulatory mechanisms not only sheds light on fundamental aspects of inflammation but also offers potential therapeutic avenues for inflammatory disorders and infectious diseases.

Periodontitis is a chronic inflammatory disease characterized by bacterial infection and immune dysregulation. Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is a key pathogen linked to disease progression. Caspase-1 and caspase-4 regulate inflammasome activation and cytokine release, yet their roles in gingival epithelial immunity remain unclear. The aim of this study was to elucidate the involvement of caspase-1 and caspase-4 in regulating the immune response to A. actinomycetemcomitans infection in gingival epithelial cells. Human gingival epithelial cells (Ca9-22) and caspase-1- and caspase-4-deficient cells were infected with A. actinomycetemcomitans for 24 h. Inflammatory mediator release was analyzed using Olink proteomics. Bacterial colonization and invasion were assessed using fluorescence-based assays and gentamicin protection assays. Caspase-1- and caspase-4-deficient cells showed significantly altered cytokine and chemokine profiles after infection with A. actinomycetemcomitans, showing reduced IL-17C and IL-18 release. We also found an increased release of TGF-α and LIF from caspase-4-deficient cells, along with elevated levels of the chemokines IL-8, CXCL9, and CXCL10. Additionally, both caspase-1- and caspase-4-deficient cells showed increased bacterial colonization and invasion, particularly in caspase-4-deficient cells. These findings suggest that caspase-1 and caspase-4 play distinct yet essential roles in gingival epithelial immunity, regulating cytokine release, barrier integrity, and defense against A. actinomycetemcomitans colonization.

IFI16 (interferon-γ-inducible protein 16) is an innate-immune DNA sensor that detects viral dsDNA in the nucleus. It also functions as an antiviral restriction factor, playing a crucial role in regulating the latency/lytic balance of several herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV). We previously demonstrated that IFI16 achieves this by regulating the deposition of H3K9me3 marks on the KSHV genome. Here, we explored whether IFI16 impacts the KSHV latency/lytic balance through additional mechanisms. Our analysis of the IFI16 interactome revealed that IFI16 binds to the class-I HDACs, HDAC1 and HDAC2, and recruits them to the KSHV major latency protein, latency-associated nuclear antigen (LANA). Previous reports have suggested that LANA undergoes lysine acetylation through unknown mechanisms, which results in the loss of its ability to bind to the KSHV transactivator protein (RTA) promoter. However, how the LANA acetylation-deacetylation cycle is orchestrated and what effect this has on KSHV gene expression remains unknown. Here, we demonstrate that LANA, by default, undergoes post-translational acetylation, and during latency, IFI16 interacts with this acetylated LANA and recruits HDAC1/2 to it. This keeps LANA in a deacetylated form, competent in binding and repressing lytic promoters. However, during lytic reactivation, IFI16 is degraded via the proteasomal pathway, leading to the accumulation of acetylated LANA, which cannot bind to the RTA promoter. This results in the de-repression of the RTA and, subsequently, other lytic promoters, driving reactivation. These findings shed new light on the role of IFI16 in KSHV latency and suggest that KSHV utilizes the cellular IFI16-HDAC1/2 interaction to facilitate its latency.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesviruses etiologically associated with several human malignancies, including Kaposi's sarcoma, primary effusion B-cell lymphoma, and multicentric Castleman's disease. Understanding the molecular mechanisms governing the establishment and maintenance of latency in γ-herpesviruses is crucial because latency plays a pivotal role in oncogenesis and disease manifestation post-infection. Here, we have elucidated a new mechanism by which IFI16, a previously discovered antiviral restriction factor, is hijacked by KSHV to recruit class-I HDACs on latency-associated nuclear antigen (LANA), resulting in the latter's deacetylation. The acetylation status of LANA is critical for KSHV latency because it governs LANA's binding to the KSHV replication and transcription activator (RTA) promoter, an immediate-early gene crucial for lytic reactivation. Depletion of IFI16 results in the accumulation of acetylated LANA, which is incapable of maintaining latency. These newly discovered interactions between IFI16 and LANA and between IFI16 and HDAC1/2 enhance our understanding of KSHV latency regulations.

Activation of the epithelial-mesenchymal transition (EMT), a pivotal process in tumor metastasis and evasion, as well as the NLRP3 inflammasome, both promote colorectal cancer (CRC) progression. Recent studies have shown that Transmembrane protein 176B (TMEM176B) regulates NLRP3 and promotes CRC malignant phenotypes.

To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.

CRC in situ mouse and co-cultured cell models were established using CT26 cells, BALB/c mice, and primary cultured mouse natural killer (NK) cells. Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells. Fluorescence imaging, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays, immunohistochemistry staining, flow cytometry, and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis, apoptosis, and EMT indicators.

Silencing TMEM176B in CRC mice significantly reduced tumor metastasis, proliferation, and EMT, while activating apoptosis, NLRP3 inflammasome, and NK cell activity. Furthermore, silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion, and promoted apoptosis. The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65, matrix metallopeptidase 9, and transforming growth factor-β.

This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.

Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Transformation of pro-interleukin (IL)-1β into a mature IL-1β via active inflammasome may be related to the progression of PD. Therefore, the modification of inflammasome activity may be a potential therapeutic strategy for PD. Inosine has been shown to exert anti-inflammatory effects in various disease models. In this study, we evaluated inosine's inhibitory effects on the microglial NLRP3 inflammasome, which may be related to the dopaminergic neuroprotective effects of inosine. Inosine suppresses lipopolysaccharides (LPS)-induced NLRP3 inflammasome activation in BV-2 microglial cells dose dependently. When SH-SY5Y cells were treated with conditioned medium from BV-2 cells treated with LPS and inosine, an NLRP3 inhibitor, or a caspase-1 inhibitor, the viability of SH-SY5Y cells was reduced indicating that LPS-induced microglial inflammasome activation could contribute to neuronal death. Inosine's modulatory effect on NLRP3 inflammasome activity appears to rely on the adenosine A2A and A3 receptors activation, as A2A or A3 receptor antagonists reversed the amelioration of NLRP3 activation by inosine. In addition, inosine treatment attenuated intracellular and mitochondrial ROS production mediated by LPS and this effect might be related to attenuation of NLRP3 inflammasome activity, as the antioxidant, N-acetyl cysteine ameliorated LPS-induced activation of the inflammasome. Finally, we assessed the inosine's neuroprotective effects via inflammasome activity modulation in mice receiving an intranigral injection of LPS. Immunohistochemical analysis revealed that LPS caused a significant loss of nigral dopaminergic neurons, which was mitigated by inosine treatment. LPS increased NLRP3 expression in IBA1-positive microglial cells, which was attenuated by inosine injection. These findings indicate that inosine can rescue neurons from LPS-induced injury by ameliorating NLRP3 inflammasome activity. Therefore, inosine could be applied as an intervention for neuroinflammatory diseases such as Parkinson's disease.