Innate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease

Regulated cell death (RCD) triggered by innate immune activation is an important strategy for host survival during pathogen invasion and perturbations of cellular homeostasis. There are two main categories of RCD, including nonlytic and lytic pathways. Apoptosis is the most well-characterized nonlytic RCD, and the inflammatory pyroptosis and necroptosis pathways are among the best known lytic forms. While these were historically viewed as independent RCD pathways, extensive evidence of cross-talk among their molecular components created a knowledge gap in our mechanistic understanding of RCD and innate immune pathway components, which led to the identification of PANoptosis. PANoptosis is a unique innate immune inflammatory RCD pathway that is regulated by PANoptosome complexes upon sensing pathogens, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) or the cytokines produced downstream. Cytosolic innate immune sensors and regulators, such as ZBP1, AIM2 and RIPK1, promote the assembly of PANoptosomes to drive PANoptosis. In this review, we discuss the molecular components of the known PANoptosomes and highlight the mechanisms of PANoptosome assembly, activation and regulation identified to date. We also discuss how PANoptosomes and mutations in PANoptosome components are linked to diseases. Given the impact of RCD, and PANoptosis specifically, across the disease spectrum, improved understanding of PANoptosomes and their regulation will be critical for identifying new therapeutic targets and strategies.     

基于NLRP3炎症小体调控细胞焦亡探讨瘀血痹抗动脉粥样硬化的作用机制

动脉粥样硬化(atherosclerosis, AS)以慢性炎症和增殖过程为特征,而细胞焦亡与AS的发生发展密切相关。核因子κB(nuclear factor kappa-B,NF-κB)的激活可以诱导白介素-1β前体(pro-IL-1β)、白介素-18前体(pro-IL-18)和增加核苷酸结合寡聚化结构域样受体蛋白3(NOD-like receptor protein 3,NLRP3)炎症小体的合成,从而触发半胱氨酸天冬氨酸蛋白酶1前体(pro-Caspase-1)蛋白水解为有活性的半胱氨酸天冬氨酸蛋白酶1(Caspase-1),Caspase-1将细胞因子前体pro-IL-1β和pro-IL-18分别转化为成熟的和具有生物活性的白介素-1β(IL-1β)和白介素-18(IL-18),参与AS形成过程,同时活性Caspase-1可以诱发细胞焦亡,前期研究发现瘀血痹能够减少ApoE^-/-小鼠主动脉斑块面积,但机制尚不清楚,同时瘀血痹药物成分可以调节NF-κB、NLRP3、IL-1β等相关因子。因此,拟从NF-κB/NLRP3/IL-1β信号通路介导的细胞焦亡探究瘀血痹抗AS的作用机制,为AS防治提供新的治疗策略。     

Rescuing fertility during COVID-19 infection: exploring potential pharmacological and natural therapeutic approaches for comorbidity,by focusing on NLRP3 inflammasome mechanism.

The respiratory system was primarily considered the only organ affected by Coronavirus disease 2019 (COVID-19). As the pandemic continues, there is an increasing concern from the scientific community about the future effects of the virus on male and female reproductive organs, infertility, and, most significantly, its impact on the future generation. The general presumption is that if the primary clinical symptoms of COVID-19 are not controlled, we will face several challenges, including compromised infertility, infection-exposed cryopreserved germ cells or embryos, and health complications in future generations, likely connected to the COVID-19 infections of parents and ancestors. In this review article, we dedicatedly studied severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) virology, its receptors, and the effect of the virus to induce the activation of inflammasome as the main arm of the innate immune response. Among inflammasomes, nucleotide oligomerization domain-like receptor protein, pyrin domain containing 3 (NLRP3) inflammasome pathway activation is partly responsible for the inflicted damages in both COVID-19 infection and some reproductive disorders, so the main focus of the discussion is on NLRP3 inflammasome in the pathogenesis of COVID-19 infection alongside in the reproductive biology. In addition, the potential effects of the virus on male and female gonad functions were discussed, and we further explored the potential natural and pharmacological therapeutic approaches for comorbidity via NLRP3 inflammasome neutralization to develop a hypothesis for averting the long-term repercussions of COVID-19. Since activation of the NLRP3 inflammasome pathway contributes to the damage caused by COVID-19 infection and some reproductive disorders, NLRP3 inflammasome inhibitors have a great potential to be considered candidates for alleviating the pathological effects of the COVID-19 infection on the germ cells and reproductive tissues. This would impede the subsequent massive wave of infertility that may threaten the patients.     

Pathogenesis of acute stroke and the role of inflammasomes

Inflammation is an innate immune response to infection or tissue damage that is designed to limit harm to the host, but contributes significantly to ischemic brain injury following stroke. The inflammatory response is initiated by the detection of acute damage via extracellular and intracellular pattern recognition receptors, which respond to conserved microbial structures, termed pathogen-associated molecular patterns or host-derived danger signals termed damage-associated molecular patterns. Multi-protein complexes known as inflammasomes (e.g. containing NLRP1, NLRP2, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, AIM2 and/or Pyrin), then process these signals to trigger an effector response. Briefly, signaling through NLRP1 and NLRP3 inflammasomes produces cleaved caspase-1, which cleaves both pro-IL-1β and pro-IL-18 into their biologically active mature pro-inflammatory cytokines that are released into the extracellular environment. This review will describe the molecular structure, cellular signaling pathways and current evidence for inflammasome activation following cerebral ischemia, and the potential for future treatments for stroke that may involve targeting inflammasome formation or its products in the ischemic brain.     

Regulation and functions of NLRP3 inflammasome during influenza virus infection

The NLRP3 inflammasome constitutes a major antiviral host defense mechanism during influenza virus infection. Inflammasome assembly in virus-infected cells facilitates autocatalytic processing of pro-caspase-1 and subsequent cleavage and secretion of proinflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome is critical for induction of both innate and adaptive immune responses during influenza virus infection. Inflammasome-dependent antiviral responses also regulate immunopathology and tissue repair in the infected lungs. The regulation of NLRP3 inflammasome assembly is an area of active research and recent studies have unraveled multiple cellular and viral factors involved in inflammasome assembly. Emerging studies have also identified the cross talk between inflammasome activation and programmed cell death pathways in influenza virus-infected cells. Here, we review the current literature regarding regulation and functions of NLRP3 inflammasome during influenza virus infection.     

The inflammasome: Learning from bacterial evasion strategies

The innate immune system plays a critical role in defense against microbial infection and employs germline-encoded pattern recognition receptors to detect broadly conserved microbial structures or activities. Pattern recognition receptors of the nucleotide binding domain/leucine rich repeat (NLR) family respond to particular microbial products or disruption of cellular physiology, and mediate the activation of an arm of the innate immune response termed the inflammasome. Inflammasomes are multiprotein complexes that are inducibly assembled in response to the contamination of the host cell cytosol by microbial products. Individual NLRs sense the presence of their cognate stimuli, and initiate assembly of inflammasomes via the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the effector pro-enzyme caspase-1. Inflammasome activation leads to rapid release of pro-inflammatory mediators of the IL-1 family as well as the release of intracellular alarmins due to a lytic form of programmed cell death termed pyroptosis. Over the past 15 years, a great deal has been learned about the mechanisms that drive inflammasome activation in response to infection by diverse pathogens. However, pathogens have also evolved mechanisms to evade or suppress host defenses, and the mechanisms by which pathogens evade inflammasome activation are not well-understood. Here, we will discuss emerging evidence on how diverse pathogens evade inflammasome activation, and what these studies have revealed about inflammasome biology. Deeper understanding of pathogen evasion of inflammasome activation has the potential to lead to development of novel classes of immunomodulatory factors that could be used in the context of human inflammatory diseases.