ADAR1 and ZBP1 are mammalian interferon-inducible proteins containing Zα domains that regulate innate immune responses across development and disease.Mutations in ADAR1 are associated with several ...autoimmune and autoinflammatory disorders in humans, such as Aicardi-Goutières Syndrome 6, systemic lupus erythematosus, and bilateral striatal necrosis.There is a regulatory relationship between ADAR1 and ZBP1 in mammalian cells, where ADAR1 suppresses ZBP1-mediated inflammatory cell death, PANoptosis.ZBP1-mediated PANoptosis contributes to the pathology caused by impaired ADAR1 function in mice.Using nuclear export inhibitors to sequester ADAR1 in the nucleus and disrupt the cytoplasmic interaction between ADAR1 and ZBP1, and activating ZBP1 through the induction of dsRNA have shown promise in preclinical mouse models.
ADAR1 and ZBP1 are the only two mammalian Zα-containing proteins; they regulate innate immune responses crucial for survival, development, and host defense against infection, inflammatory diseases, and cancers. While the interaction of ADAR1 with ZBP1 suppresses cell death, the interaction of RIPK3 with ZBP1 drives innate immune inflammatory cell death (i.e., PANoptosis). Molecules that can modulate the ADAR1-ZBP1 or RIPK3-ZBP1 interaction have therapeutic potential for the treatment of inflammatory and infectious diseases.
ADAR1 and ZBP1 are the only two mammalian proteins that contain Zα domains, which are thought to bind to nucleic acids in the Z-conformation. These two molecules are crucial in regulating diverse biological processes. While ADAR1-mediated RNA editing supports host survival and development, ZBP1-mediated immune responses provide host defense against infection and disease. Recent studies have expanded our understanding of the functions of ADAR1 and ZBP1 beyond their classical roles and established their fundamental regulation of innate immune responses, including NLRP3 inflammasome activation, inflammation, and cell death. Their roles in these processes have physiological impacts across development, infectious and inflammatory diseases, and cancer. In this review, we discuss the functions of ADAR1 and ZBP1 in regulating innate immune responses in development and disease.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Activation of the NLRC4 inflammasome is crucial for defense against bacterial species that have flagellin or the type III secretion system (T3SS). We have discovered the role of interferon regulatory ...factor 8 (IRF8) in mediating NLRC4 inflammasome activation. IRF8 is required for the transcription of genes encoding NAIPs, thereby enabling cellular detection of flagellin or T3SS proteins.
, IRF8 is important for NLRC4 inflammasome-dependent cytokine production, bacterial clearance, and ultimately, host survival. By introducing IRF8 as a player in inflammasome regulation, our study provides a new perspective on that process.
Inflammasomes are important sentinels of innate immune defence, sensing pathogens and inducing cell death in infected cells.sup.1. There are several inflammasome sensors that each detect and respond ...to a specific pathogen- or damage-associated molecular pattern (PAMP or DAMP, respectively).sup.1. During infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which can simultaneously engage multiple inflammasome sensors.sup.2-5. Here we found that AIM2 regulates the innate immune sensors pyrin and ZBP1 to drive inflammatory signalling and a form of inflammatory cell death known as PANoptosis, and provide host protection during infections with herpes simplex virus 1 and Francisella novicida. We also observed that AIM2, pyrin and ZBP1 were members of a large multi-protein complex along with ASC, caspase-1, caspase-8, RIPK3, RIPK1 and FADD, that drove inflammatory cell death (PANoptosis). Collectively, our findings define a previously unknown regulatory and molecular interaction between AIM2, pyrin and ZBP1 that drives assembly of an AIM2-mediated multi-protein complex that we term the AIM2 PANoptosome and comprising multiple inflammasome sensors and cell death regulators. These results advance the understanding of the functions of these molecules in innate immunity and inflammatory cell death, suggesting new therapeutic targets for AIM2-, ZBP1- and pyrin-mediated diseases.
Full text
Available for:
GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The innate immune response provides the first line of defense against infection and disease. Regulated cell death (RCD) is a key component of innate immune activation, and RCD must be tightly ...controlled to clear pathogens while preventing excess inflammation. Recent studies have highlighted a central role for the innate immune sensor Z-DNA-binding protein 1 (ZBP1) as an activator of a form of inflammatory RCD called PANoptosis, which is regulated by a multifaceted cell death complex called the PANoptosome. In response to influenza A virus infection, ZBP1 activates the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, which then acts as an integral component of the ZBP1-PANoptosome to drive inflammatory cell death, PANoptosis. In this context, the NLRP3 inflammasome is critical for caspase-1 activation and proinflammatory cytokine interleukin (IL)-1β and IL-18 maturation, but dispensable for cell death due to functional redundancies between PANoptosome molecules. Similarly, ZBP1 is also central to the absent in melanoma 2 (AIM2)-PANoptosome; this PANoptosome forms in response to Francisella novicida and herpes simplex virus 1 infection and incorporates the AIM2 inflammasome as an integral component. In this review, we will discuss the critical roles of ZBP1 in mediating innate immune responses through inflammasomes, PANoptosomes, and PANoptosis during infection. An improved understanding of the molecular mechanisms of innate immunity and cell death will be essential for the development of targeted modalities that can improve patient outcomes by mitigating severe disease.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate ...immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.
Display omitted
•Of several cytokines tested, only synergism of TNF-α and IFN-γ induces PANoptosis•TNF-α and IFN-γ-mediated PANoptosis perpetuates cytokine storm•TNF-α and IFN-γ shock mirrors cytokine storm syndromes, including COVID-19•Neutralizing TNF-α and IFN-γ protects against SARS-CoV-2, HLH, and sepsis in mice
TNF-α and IFN-γ synergize to drive the cytokine storm and cell death associated with COVID-19 and sepsis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development ...of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis-associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we have shown that Il33-deficient mice are highly susceptible to colitis and CAC. Mechanistically, we observed that IL-33 promoted IgA production from B cells, which is important for maintaining microbial homeostasis in the intestine. Il33-deficient mice developed a dysbiotic microbiota that was characterized by increased levels of mucolytic and colitogenic bacteria. In response to chemically induced colitis, this microbial landscape promoted the release of IL-1α, which acted as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1α ablation markedly ameliorated colitis susceptibility in Il33-deficient animals. Our results demonstrate that IL-33 promotes IgA production to maintain gut microbial homoeostasis and restrain IL-1α-dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1α, and the microbiota as a potential therapeutic approach in the treatment of IBD and CAC.
Abstract
Interferon regulatory factor 1 (IRF1) is a transcription factor that is induced in response to interferons and inflammatory cytokines. We have previously identified the role of IRF1 in ...mediating inflammasome activation. These inflammasomes are associated with providing protective responses against colorectal tumorigenesis. The relevance of IRF1 to the immunobiology of cancer is still emerging, and the crucial role of IRF1 in colorectal cancer (CRC) remains unknown. The multiple inflammatory mediators produced during colorectal tumorigenesis have the ability to mediate cellular death; this may represent alternative forms of apoptosis that cannot readily be recapitulated in vitro by using classical apoptosis inducers. The precise regulatory mechanisms by which IRF1 governs the activation of cell death in response to inflammatory milieu remains elusive. Given that IRF1 is a transcription factor, it may induce the expression of upstream cell death mediators that are dependent on cytokines and that subsequently activate the executioner caspases. Here, we found that Irf1−/− mice were hyper-susceptible to CRC. IRF1 played roles in both myeloid and epithelial compartments to confer protection against CRC. Interestingly, IRF1 did not regulate inflammatory cytokines production and inflammasome activation in colons. However, IRF1 promoted cell death mediated by the inflammatory cytokines. The decreased cell death in the colons of Irf1−/− mice was associated with impaired activation of apoptotic caspases. Mechanistically, we demonstrated that IRF1 deficiency attenuated the induction of Fas and activation of caspase-8 that lead to reduced effector caspase-3 and caspase-7 activation in the colons.
Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death ...(pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 in response to
subspecies
infection, leading to maturation of IL-1β and IL-18 and pyroptosis. AIM2 is ...critical for host protection against
infection in vivo; however, the role of pyroptosis downstream of the AIM2 inflammasome is unknown. Recent studies have identified gasdermin D (GSDMD) as the molecule executing pyroptosis by forming pores on the plasma membrane following activation by inflammatory caspase-1 and -11. In this study, we report that GSDMD-deficient mice were susceptible to
infection compared with wild type mice. Interestingly, we observed that GSDMD is required for optimal caspase-1 activation and pyroptotic cell death in
-infected bone marrow-derived macrophages. Furthermore, caspase-1 activation was compromised in bone marrow-derived macrophages lacking GSDMD stimulated with other AIM2 inflammasome triggers, including poly(dA:dT) transfection and mouse CMV infection. Overall, our study highlights a function, to our knowledge previously unknown, for GSDMD in promoting caspase-1 activation by AIM2 inflammasome.
Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune ...responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8– and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)–mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
