Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by chronic inflammation and immune dysregulation, significantly impacting multiple organ systems, including the joints. While SLE is known to contribute to musculoskeletal complications, its role in hip arthritis development and the underlying mechanisms remain poorly understood. This study aims to investigate the relationship between SLE and hip arthritis progression using MRL/lpr mice, which exhibit early-onset SLE, compared with MRL/MpJ control mice at 14 weeks of age. Through comprehensive histological, immunohistochemical and molecular analyses, we evaluated articular cartilage (AC) degeneration, extracellular matrix (ECM) metabolism, inflammatory responses, and chondrocyte pyroptosis. Our results demonstrated that MRL/lpr mice developed an accelerated hip arthritis-like phenotype, manifesting as enhanced AC degeneration, impaired chondrocyte proliferation, heightened apoptosis and promoted inflammatory cytokine production. Notably, SLE markedly stimulated chondrocyte pyroptosis by increasing pyroptosis-related proteins, including NLRP3, ASC, CASPASE-1 and GSDMD, via activating the NF-κB pathway. These findings establish a novel mechanistic link between SLE and hip arthritis progression, demonstrating that SLE promotes chondrocyte pyroptosis to exacerbate AC degeneration via NF-κB activation, highlighting chondrocyte pyroptosis as a key driver of SLE-associated hip arthritis and a potential therapeutic target for mitigating SLE-induced joint manifestations.

Caspase-8, a renowned cysteine-aspartic protease within its enzyme family, initially garnered attention for its regulatory role in extrinsic apoptosis. With advancing research, a growing body of evidence has substantiated its involvement in other cell death processes, such as pyroptosis and necroptosis, as well as its modulatory effects on inflammasomes and proinflammatory cytokines. PANoptosis, an emerging concept of cell death, encompasses pyroptosis, apoptosis, and necroptosis, providing insight into the often overlapping cellular mortality observed during disease progression. The activation or deficiency of caspase-8 enzymatic activity is closely linked to PANoptosis, positioning caspase-8 as a key regulator of cell survival or death across various physiological and pathological processes. Aberrant expression of caspase-8 is closely associated with the development and progression of a range of inflammatory diseases, including immune system disorders, neurodegenerative diseases (NDDs), sepsis, and cancer. This paper delves into the regulatory role and impact of caspase-8 in these conditions, aiming to elucidate potential therapeutic strategies for the future intervention.

Fas ligand (FasL, CD178) belongs to classical apoptotic molecules, however, recent evidence expands the spectrum of FasL functions into non-apoptotic processes which also applies for the bone. Tgfb subfamily members (Tgfb1, Tgfb2, Tgfb3) represent major components in osteogenic pathways and extracellular matrix. Their possible association with FasL has not yet been investigated but can be postulated. To test such a hypothesis, FasL deficient (gld) calvaria-derived cells were examined with a focus on the expression of Tgfb receptor ligands. The qPCR analysis revealed significantly increased expression of Tgfb1, Tgfb2 and Tgfb3 in gld cells. To check the vice versa effect, the gld cells were stimulated by soluble FasL. As a consequence, a dramatic decrease in expression levels of all three ligands was observed. This phenomenon was also confirmed in IDG-SW3 (osteoblastic cells of endochondral origin). TFLink gateway identified Fosl2 as an exclusive candidate of FasL capable to impact expression of all three Tgfb ligands. However, Fosl2 siRNA did not cause any significant changes in expression of Tgfb ligands. Therefore, the upregulation of the three ligands is likely to occur separately. In this respect, we tested the only exclusive candidate transcription factor for Tgfb3, Prrx1. Additionally, an overlapping candidate for Tgfb1 and Tgfb2, Mef2c capable to modulate expression of sclerostin, was examined. Prrx1 as well as Mef2c were found upregulated in gld samples and their expression decreased after addition of FasL. The same effect of FasL treatment was observed in the IDG-SW3 model. Taken together, FasL deficiency causes an increase in the expression of Tgfb ligands and stimulation by FasL reduces Tgfb expression in osteoblastic cells. The candidates mediating the effect comprise Prrx1 for Tgfb3 and Mef2c for Tgfb1/2. These results indicate FasL as a novel cytokine interfering with Tgfb signaling and thus the complex osteogenic network. The emerging non-apoptotic functions of FasL in bone development and maintenance should also be considered in treatment strategies such as the anti-osteoporotic factor.

The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1ΔCD4) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4+, naive CD8+, and FoxP3+ regulatory T cells. Interestingly, peripheral naive CD8+ T cells in Ripk1ΔCD4 mice appear to undergo a selective pressure to retain RIPK1 expression following activation. Mixed bone marrow chimeras revealed a competitive survival disadvantage for naive, effector, and memory T cells lacking RIPK1. Additionally, tamoxifen-induced deletion of RIPK1 in CD4-expressing cells in adult life confirmed the importance of RIPK1 in post-thymic survival of CD4+ T cells. Ripk1K45A mice showed no change in peripheral T cell subsets, demonstrating that the T cell lymphopenia was due to the scaffold function of RIPK1 rather than to its kinase activity. Enhanced numbers of Ripk1ΔCD4 naive T cells expressed the proliferation marker Ki-67+ despite the peripheral lymphopenia and single-cell RNA sequencing revealed T cell-specific transcriptomic alterations that were reverted by additional caspase-8 deficiency. Furthermore, Ripk1ΔCD4Casp8 ΔCD4 and Ripk1ΔCD4Tnfr1-/- double-knockout mice rescued the peripheral T cell lymphopenia, revealing that RIPK1-deficient naive CD4+ and CD8+ cells and FoxP3+ regulatory T cells specifically die from TNF- and caspase-8-mediated apoptosis in vivo. Altogether, our findings emphasize the essential role of RIPK1 as a scaffold in maintaining the peripheral T cell compartment and preventing TNFR1-induced apoptosis.

Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.

Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed suicide mechanisms of apoptosis, necroptosis, and pyroptosis, or it can be a consequence of dysregulated metabolism, as in ferroptosis. Here, we review the signaling mechanisms underlying each cell-death pathway, discuss how impaired or excessive activation of the distinct cell-death processes can promote disease, and highlight existing and potential therapies for redressing imbalances in cell death in cancer and other diseases.

p53 is a transcription factor that regulates the expression of genes involved in tumor suppression. p53 mutations mediate tumorigenesis and occur in approximately 50% of human cancers. p53 regulates hundreds of target genes that induce various cell fates including apoptosis, cell cycle arrest, and DNA damage repair. p53 also plays an important role in anti-tumor immunity by regulating TRAIL, DR5, TLRs, Fas, PKR, ULBP1/2, and CCL2; T-cell inhibitory ligand PD-L1; pro-inflammatory cytokines; immune cell activation state; and antigen presentation. Genetic alteration of p53 can contribute to immune evasion by influencing immune cell recruitment to the tumor, cytokine secretion in the TME, and inflammatory signaling pathways. In some contexts, p53 mutations increase neoantigen load which improves response to immune checkpoint inhibition. Therapeutic restoration of mutated p53 can restore anti-cancer immune cell infiltration and ameliorate pro-tumor signaling to induce tumor regression. Indeed, there is clinical evidence to suggest that restoring p53 can induce an anti-cancer immune response in immunologically cold tumors. Clinical trials investigating the combination of p53-restoring compounds or p53-based vaccines with immunotherapy have demonstrated anti-tumor immune activation and tumor regression with heterogeneity across cancer type. In this Review, we discuss the impact of wild-type and mutant p53 on the anti-tumor immune response, outline clinical progress as far as activating p53 to induce an immune response across a variety of cancer types, and highlight open questions limiting effective clinical translation.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death - including apoptosis and necrosis - have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.

Monogenic autoimmune disorders represent an important tool to understand the mechanisms behind central and peripheral immune tolerance. Multiple factors, both genetic and environmental, are known to be involved in the alteration of the immune activation/immune tolerance homeostasis typical of these disorders, making it difficult to control the disease. The latest advances in genetic analysis have contributed to a better and more rapid diagnosis, although the management remains confined to the treatment of clinical manifestations, as there are limited studies on rare diseases. Recently, the correlation between microbiota composition and the onset of autoimmune disorders has been investigated, thus opening up new perspectives on the cure of monogenic autoimmune diseases. In this review, we will summarize the main genetic features of both organ-specific and systemic monogenic autoimmune diseases, reporting on the available literature data on microbiota alterations in these patients.

Co-stimulation signaling in various types of immune cells modulates immune responses in physiology and disease. Tumor necrosis factor receptor superfamily (TNFRSF) members such as CD40, OX40 and CD137/4-1BB are expressed on myeloid cells and/or lymphocytes, and they regulate antigen presentation and adaptive immune activities. TNFRSF agonistic antibodies have been evaluated extensively in preclinical models, and the robust antitumor immune responses and efficacy have encouraged continued clinical investigations for the last two decades. However, balancing the toxicities and efficacy of TNFRSF agonistic antibodies remains a major challenge in the clinical development. Insights into the co-stimulation signaling biology, antibody structural roles and their functionality in immuno-oncology are guiding new advancement of this field. Leveraging the interactions between antibodies and the inhibitory Fc receptor FcγRIIB to optimize co-stimulation agonistic activities dependent on FcγRIIB cross-linking selectively in tumor microenvironment represents the current frontier, which also includes cross-linking through tumor antigen binding with bispecific antibodies. In this review, we will summarize the immunological roles of TNFRSF members and current clinical studies of TNFRSF agonistic antibodies. We will also cover the contribution of different IgG structure domains to these agonistic activities, with a focus on the role of FcγRIIB in TNFRSF cross-linking and clustering bridged by agonistic antibodies. We will review and discuss several Fc-engineering approaches to optimize Fc binding ability to FcγRIIB in the context of proper Fab and the epitope, including a cross-linking antibody (xLinkAb) model and its application in developing TNFRSF agonistic antibodies with improved efficacy and safety for cancer immunotherapy.

The germinal center serves as a site of B cell selection and affinity maturation, critical processes for productive adaptive immunity. In autoimmune disease tolerance is broken in the germinal center reaction, leading to production of autoreactive B cells that may propagate disease. Follicular T cells are crucial regulators of this process, providing signals necessary for B cell survival in the germinal center. Here we review the emerging roles of follicular T cells in the autoreactive germinal center. Recent advances in immunological techniques have allowed study of the gene expression profiles and repertoire of follicular T cells at unprecedented resolution. These studies provide insight into the potential role follicular T cells play in preventing or facilitating germinal center loss of tolerance. Improved understanding of the mechanisms of T cell help in autoreactive germinal centers provides novel therapeutic targets for diseases of germinal center dysfunction.

Adaptive immune responses rely on the proliferation of T lymphocytes able to recognize and eliminate pathogens. The magnitude and duration of the expansion of activated T cell clones are finely regulated to minimize immunopathology and avoid autoimmunity. In patients with rheumatic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, activated lymphocytes survive and exert effector functions for prolonged periods, defying the mechanisms that normally curb their capacities during acute and chronic infections. Here, we review the molecular mechanisms that limit the duration of immune responses in health and discuss the factors that alter such regulation in the setting of systemic lupus erythematosus and rheumatoid arthritis. We highlight defects that could contribute to the development and progression of autoimmune disease and describe how chronic inflammation can alter the regulation of activated lymphocyte survival, promoting its perpetuation. These concepts might contribute to the understanding of the mechanisms that underlie the chronicity of inflammation in the context of autoimmunity.

Cell death plays a pivotal role in the maintenance of tissue homeostasis. Key players in the controlled induction of cell death are the Death Receptors (DR). CD95 is a prototypic DR activated by its cognate ligand CD95L triggering programmed cell death. As a consequence, alterations in the CD95/CD95L pathway have been involved in several disease conditions ranging from autoimmune diseases to inflammation and cancer. CD95L-induced cell death has multiple roles in the immune response since it constitutes one of the mechanisms by which cytotoxic lymphocytes kill their targets, but it is also involved in the process of turning off the immune response. Furthermore, beyond the canonical pro-death signals, CD95L, which can be membrane-bound or soluble, also induces non-apoptotic signaling that contributes to its tumor-promoting and pro-inflammatory roles. The intent of this review is to describe the role of CD95/CD95L in the pathophysiology of cancers, autoimmune diseases and chronic inflammation and to discuss recently patented and emerging therapeutic strategies that exploit/block the CD95/CD95L system in these diseases.

Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell death, can occur in both separate and simultaneous manners. ATM (ataxia telangiectasia mutated) kinase (hereafter referred to as ATM) is a protein kinase that plays central roles in the induction of cell death during genotoxic stresses. It has long been considered that ATM mediates DNA damage-induced cell death through inducing apoptosis. However, recent research progress in cell death modality is now revealing ATM-dependent cell death pathways that consist of not only apoptosis but also necroptosis, ferroptosis, and dysfunction of autophagy, a cellular survival mechanism. In this short review, we intend to provide a brief outline of cell death mechanisms in which ATM is involved, with emphasis on pathways other than apoptosis.

In the last decade, the role of apoptosis in the pathophysiology of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) progression has been revisited as our understanding of ferroptosis and necroptosis has emerged. A growing body of evidence, reviewed here, ascribes a central pathophysiological role for ferroptosis and necroptosis to AKI, nephron loss, and acute tubular necrosis. We will introduce concepts to the non-cell-autonomous manner of kidney tubular injury during ferroptosis, a phenomenon that we refer to as a "wave of death." We hypothesize that necroptosis might initiate cell death propagation through ferroptosis. The remaining necrotic debris requires effective removal processes to prevent a secondary inflammatory response, referred to as necroinflammation. Open questions include the differences in the immunogenicity of ferroptosis and necroptosis, and the specificity of necrostatins and ferrostatins to therapeutically target these processes to prevent AKI-to-CKD progression and end-stage renal disease.

Programmed cell death (PCD) is a requisite feature of development and homeostasis but can also be indicative of infections, injuries, and pathologies. In concordance with these heterogeneous contexts, an array of disparate effector responses occur downstream of cell death and its clearance-spanning tissue morphogenesis, homeostatic turnover, host defense, active dampening of inflammation, and tissue repair. This raises a fundamental question of how a single contextually appropriate response ensues after an event of PCD. To explore how complex inputs may together tailor the specificity of the resulting effector response, here we consider (a) the varying contexts during which different cell death modalities are observed, (b) the nature of the information that can be passed on by cell corpses, and (c) the ways by which efferocyte populations synthesize signals from dying cells with those from the surrounding microenvironment.

B lymphocytes make several contributions to immune regulation including production of antibodies with regulatory properties, release of immune suppressive cytokines, and expression of death-inducing ligands. A role for Fas ligand (FasL)-expressing "killer" B cells in regulating T helper (T_H) cell survival and chronic inflammation has been demonstrated in animal models of schistosome worm and other infections, asthma, autoimmune arthritis, and type 1 diabetes. FasL⁺ B cells were also capable of inducing immune tolerance in a male-to-female transplantation model. Interestingly, populations of B cells found in the spleen and lungs of naïve mice constitutively expresses FasL and have potent killer function against T_H cells that is antigen-specific and FasL-dependent. Epstein-Barr virus-transformed human B cells constitutively express FasL and package it into exosomes that co-express MHC Class II molecules and have killer function against antigen-specific T_H cells. FasL⁺ exosomes with markers of B-cell lineage are abundant in the spleen of naïve mice. Killer B cells therefore represent a novel target for immune modulation in many disease settings. Our laboratory has published methods of characterizing FasL⁺ B cells and inducing their proliferation in vitro. This updated chapter will describe methods of identifying and expanding killer B cells from mice, detecting FasL expression in B cells, extracting FasL⁺ exosomes from spleen and culture supernatants, and performing functional killing assays against antigen-specific T_H cells.

Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αβ+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.

The authors are reporting a case of autoimmune lymphoproliferative syndrome in a newborn who presented with massive hepatosplenomegaly, thrombocytopenia, and anemia at birth. Antenatal ultrasound revealed a fetus with hepatosplenomegaly. The infant was treated with steroids and sirolimus and is doing well at 4 years of age. This is the first case report of autoimmune lymphoproliferative syndrome presenting as hepatosplenomegaly during fetal life.

Fas ligand (FasL) is best known for its ability to induce cell death in a wide range of Fas-expressing targets and to limit inflammation in immunoprivileged sites such as the eye. In addition, the ability of FasL to induce a much more extensive list of outcomes is being increasingly explored and accepted. These outcomes include the induction of proinflammatory cytokine production, T cell activation, and cell motility. However, the distinct and opposing functions of membrane-associated FasL (mFasL) and the C-terminal soluble FasL fragment (sFasL) released by metalloproteinase cleavage is less well documented and understood. Both mFasL and sFasL can form trimers that engage the trimeric Fas receptor, but only mFasL can form a multimeric complex in lipid rafts to trigger apoptosis and inflammation. By contrast, a number of reports have now documented the anti-apoptotic and anti-inflammatory activity of sFasL, pointing to a critical regulatory function of the soluble molecule. The immunomodulatory activity of FasL is particularly evident in ocular pathology where elimination of the metalloproteinase cleavage site and the ensuing increased expression of mFasL can severely exacerbate the extent of inflammation and cell death. By contrast, both homeostatic and increased expression of sFasL can limit inflammation and cell death. The mechanism(s) responsible for the protective activity of sFasL are discussed but remain controversial. Nevertheless, it will be important to consider therapeutic applications of sFasL for the treatment of ocular diseases such as glaucoma.

In the immune system, T lymphocytes undergo rapid clonal expansion upon pathogen infection. Following pathogen clearance, most of proliferated T cells will be eliminated by the apoptosis pathway to keep the balance of immune cells. FASLG, by interacting with its cognate receptor FAS, plays a major role in controlling the T cell death. FASLG is a type II transmembrane protein, with its C-terminal extracellular domain responsible for interacting with FAS. The N-terminal cytosolic region, despite short and intrinsically disordered, plays critical roles on the protein stability and transportation. The correct localization, either on the plasma membrane or secreted with exosome, or shed into the extracellular region after protease cleavage, has a great impact on the proper function of FASLG. Following synthesis, FASLG is transported by intracellular vesicle transportation system to the final destination. In this report, ALG2, a molecule identified in the T cell apoptosis and shown to be involved in vesicle trafficking previously, was found to interact with FASLG and regulate FASLG transportation. Therefore, we identified a new regulating factor for FASLG function within T cells and also revealed a new pathway for ALG2 involvement in T cell apoptosis.

Apoptosis plays an important role in controlling the adaptive immune response and general homeostasis of the immune cells, and impaired apoptosis in the immune system results in autoimmunity and immune dysregulation. In the last 25 years, inherited human diseases of the Fas-FasL pathway have been recognized. Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity, characterized clinically by nonmalignant and noninfectious lymphoproliferation, autoimmunity, and increased risk of lymphoma due to a defect in lymphocyte apoptosis. The laboratory hallmarks of ALPS are an elevated percentage of T-cell receptor αβ double negative T cells (DNTs), elevated levels of vitamin B12, soluble FasL, IL-10, IL-18 and IgG, and defective in vitro Fas-mediated apoptosis. In order of frequency, the genetic defects associated with ALPS are germinal and somatic ALPS-FAS, ALPS-FASLG, ALPS-CASP10, ALPS-FADD, and ALPS-CASP8. Partial disease penetrance and severity suggest the combination of germline and somatic FAS mutations as well as other risk factor genes. In this report, we summarize human defects of apoptosis leading to ALPS and defects that are known as ALPS-like syndromes that can be clinically similar to, but are genetically distinct from, ALPS. An efficient genetic and immunological diagnostic approach to patients suspected of having ALPS or ALPS-like syndromes is essential because this enables the establishment of specific therapeutic strategies for improving the prognosis and quality of life of patients.

The mechanisms by which psychological stress impairs semen quality are largely unknown. By using a restraint-stressed mouse model, we studied the role of the FasL/Fas system in psychological stress-induced apoptosis of spermatozoa and spermatogenic cells. Male mice were restrained for 48 h before examination for sperm fertilizing potential and for apoptosis and FasL/Fas expression in spermatozoa, spermatogenetic cells/seminiferous tubules, and caudae epididymides. The results showed that the male restraint reduced motility, fertilization rates, and mitochondrial membrane potential while increasing apoptosis and Fas expression in spermatozoa. Restraint also facilitated apoptosis and FasL/Fas expression in spermatogenic cells/seminiferous tubules and caudae epididymides. The restraint-induced apoptosis in spermatozoa and spermatogenic cells was significantly ameliorated in gld mice that harbor a loss-of-function mutation in FasL. However, incubation with FasL did not affect sperm motility and apoptosis, while incubation with tumor necrosis factor (TNF)-α did. The epididymis of the gld mice produced significantly less TNF-α and TNF-related apoptosis-inducing ligand (TRAIL) than that of wild-type mice did after male restraint. Thus, the results confirmed that the FasL/Fas system played an important role in the psychological stress-induced apoptosis of spermatozoa and spermatogenic cells and that FasL triggered sperm apoptosis in epididymis dependently through promoting TNF-α and TRAIL secretion.

Cell death is a vital process that occurs in billions of cells in the human body every day. This process helps maintain tissue homeostasis, supports recovery from acute injury, deals with infection and regulates immunity. Cell death can also provoke inflammatory responses, and lytic forms of cell death can incite inflammation. Loss of cell membrane integrity leads to the uncontrolled release of damage-associated molecular patterns (DAMPs), which are normally sequestered inside cells. Such DAMPs increase local inflammation and promote the production of cytokines and chemokines that modulate the innate immune response. Cell death can be both a consequence and a cause of inflammation, which can be difficult to distinguish in chronic diseases. Despite this caveat, excessive or poorly regulated cell death is increasingly recognized as a contributor to chronic inflammation in rheumatic disease and other inflammatory conditions. Drugs that inhibit cell death could, therefore, be used therapeutically for the treatment of these diseases, and programmes to develop such inhibitors are already underway. In this Review, we outline pathways for the major cell death programmes (apoptosis, necroptosis, pyroptosis and NETosis) and their potential roles in chronic inflammation. We also discuss current and developing therapies that target the cell death machinery.

Laboratory animal models are beneficial when they recapitulate all or just some of the clinical and immunological manifestations of the disease. Various animals such as cats, rats, dogs, hamsters, guinea pigs, rabbits, horses, minks, pigs, and primates have been described lupus-like phenotype. However, a mouse has remained the preferable animal for scientific investigations as a result of their reduced lifespan, easy reproduction, markedly low costs, public acceptance, ease of genetic management, and the probability to stay under standardized conditions. It is highly challenging to establish a mouse model with all features of lupus because of the difficulty and the heterogeneity of the clinical features in systemic lupus erythematous (SLE). Additionally, due to the multiple differences between the mouse and human immune system, the direct translation usually fails. Each mouse model has specific characteristics and shares many subsets of aspects with the disease observed in humans, which gives researchers a tool to select their particular needs. Over 50 years, many mice models have been developed and used to dissect the pathogenesis of lupus, also to test novel drugs and therapies. In general, mice models that contribute considerably in SLE understanding can be divided into four groups: Spontaneous models, induced models, genetically modified models, along with humanizing mouse models that are the link between the mouse and human immune system. In this updated review, we will present what has been learned from different lupus mice models and how these models have contributed to a better understanding of lupus pathogenesis and treatment.

Mucosal health and disease is mediated by a complex interplay between the microbiota ("spark") and the inflammatory response ("flame"). Pathobionts, a specific class of microbes, exemplified by the oral microbe Porphyromonas gingivalis, live mostly "under the radar" in their human hosts, in a cooperative relationship with the indigenous microbiota. Dendritic cells (DCs), mucosal immune sentinels, often remain undisturbed by such microbes and do not alert adaptive immunity to danger. At a certain tipping point of inflammation, an "awakening" of pathobionts occurs, wherein their active growth and virulence are stimulated, leading to a dysbiosis. Pathobiont becomes pathogen, and commensal becomes accessory pathogen. The local inflammatory outcome is the Th17-mediated degenerative bone disease, periodontitis (PD). In systemic circulation of PD subjects, inflammatory DCs expand, carrying an oral microbiome and promoting Treg and Th17 responses. At distant peripheral sites, comorbid diseases including atherosclerosis, Alzheimer's disease, macular degeneration, chronic kidney disease, and others are reportedly induced. This review will review the immunobiology of DCs, examine the complex interplay of microbes and DCs in the pathogenesis of PD and its comorbid inflammatory diseases, and discuss the role of apoptosis and autophagy in this regard. Overall, the pathophysiological mechanisms of DC-mediated chronic inflammation and tissue destruction will be summarized.

CD95 (also known as Fas) is the prototype of death receptors; however, evidence suggests that this receptor mainly implements non-apoptotic signaling pathways such as NF-κB, MAPK, and PI3K that are involved in cell migration, differentiation, survival, and cytokine secretion. At least two different forms of CD95 L exist. The multi-aggregated transmembrane ligand (m-CD95 L) is cleaved by metalloproteases to release a homotrimeric soluble ligand (s-CD95 L). Unlike m-CD95 L, the interaction between s-CD95 L and its receptor CD95 fails to trigger apoptosis, but instead promotes calcium-dependent cell migration, which contributes to the accumulation of inflammatory Th17 cells in damaged organs of lupus patients and favors cancer cell invasiveness. Novel inhibitors targeting the pro-inflammatory roles of CD95/CD95 L may provide attractive therapeutic options for patients with chronic inflammatory disorders or cancer. This review discusses the roles of the CD95/CD95 L pair in cell migration and metastasis.

Intestinal helminths induce immune suppressive responses thought to regulate inflammatory diseases including allergies and autoimmune diseases. This study was designed to evaluate whether helminthic infections suppress the natural development of systemic lupus erythematosus (SLE) in NZBWF1 mice. Infection of NZBWF1 SLE-prone mice with two nematodes failed to establish long-lasting settlement. However, the Hymenolepis microstoma (Hm) rodent tapeworm successfully established long-term parasitization of NZBWF1 mice and was used to evaluate the suppressive effects of helminth infection. Ten-month-old NZBWF1 mice developed symptoms including autoantibody generation, proteinuria, glomerular histopathology, and splenomegaly, but mice infected with Hm at 2 months of age did not show any clinical signs. Furthermore, infection with Hm reduced lymphocyte activation and increased regulatory T cells in the spleen and mesenteric lymph nodes. These results indicate that infection with Hm protects NZBWF1 mice from naturally developing SLE and suggest that pathological immunity is attenuated, presumably because of the induction of regulatory T cells.