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Simplified schematic presentation of the two-step regulatory process of inflammasome activation and proinflammatory downstream effects in the context of autoimmune skin diseases. (A) During physiological cornification, degradation of cellular components and proteolysis occur in keratinocytes, which have the capacity to activate innate immune pathways such as the proinflammatory inflammasome with subsequent pyroptosis. Specific regulatory mechanisms such as autophagy and anti-inflammatory proteins such as IL-37, IL-38 and CARD18 can keep pyroptosis under tight control. Under the course of terminal differentiation, mRNA of pro-homeostatic acting NLRP10, IL37, IL1F10 and GSDMA is upregulated in keratinocytes, whereas mRNA of proinflammatory IL1B, IL18 and GSDMD is decreased compared to basal epidermal keratinocytes. (B) In autoimmune skin diseases, terminal differentiation and inflammasome signaling can be dysregulated. Trigger factors lead to the release of DAMPs and inflammatory cytokines in keratinocytes, entailing innate immune signaling such as inflammasome activation. In a priming step, which is not mandatory for keratinocytes, TLR, TNFR, and IFNAR are activated by DAMP/PAMP and cytokines, entailing downstream NF-κB- and JAK-STAT signaling. Upregulation of inflammasome-associated proteins (such as NLRP, NLRC4, AIM2, pro-IL1β, pro-IL18) alongside others such as ISG leads to increased susceptibility to inflammasome stimuli, which can initiate inflammasome assembly in a second “activation” step. (C) In keratinocytes, NLRP3 inflammasome can be activated by UVB radiation followed by Ca²⁺ influx, dsDNA mediated by PKR, H2O2 via ROS production, house dust mites, also named Dermatophagoides, and P2X7R-activating ATP. NLRP1 inflammasome can be activated by UVB-induced ribotoxic stress via p38 signaling, dsRNA, Staphylococcus (S.) aureus and the K⁺ specific ionophore nigericin, which leads to ROS production. NLRP10 can be activated by distinct molecular events in damaged mitochondrial organelles, independent of mtDNA. AIM2 is known to recognize nucleic acids (extracellular, cytosolic DNA/RNA motifs and mtDNA). Upon inflammasome assembly, effector molecules IL-1β, IL-18 and GSDMD are activated. Via GSDMD-executed pyroptosis, DAMPs, interleukins and other cytokines are released through the pores. (D) Thus, these molecules can exert their effector functions on neighbouring cells, e.g. keratinocytes and dendritic cells. Inflammatory cells such as macrophages invade lesional skin and dendritic cells can activate T cells resulting in an antigen-driven cellular response. Keratinocytes can undergo further forms of cell death such as apoptosis and proinflammatory necroptosis. Caspase activation and recruitment domain (CARD), Chemokine (C-C motif) ligand (CCL), Chemokine (C-X-C motif) ligand (CXCL), Dendritic cell (DC), Neutrophil granulocyte (nG), Macrophage (Mph), Plasmacytoid dendritic cell (pDC), Toll-like receptors (TLR), Tumour necrosis factor receptors (TNFR), Nucleotide-binding oligomerization domain, Interferon-α/β receptors (IFNAR), Damage-associated molecular pattern (DAMP), Pathogen-associated molecular pattern (PAMP), Myeloid differentiation primary response 88 (MYD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), IkappaB kinase (IKK), TNF receptor associated factor (TRAF), Interleukin-1 receptor-associated kinase 1 (IRAK), TANK-binding kinase 1 (TBK1), Caspase (Casp), NLR family CARD domain containing 4 (NLRC4), p38 mitogen-activated protein kinases (p38), A mitogen-activated protein kinase (MAPK), Staphylococcus aureus (S. aureus), double-stranded-RNA (dsRNA)-activated serine-threonine protein kinase (PKR), Hydrogen peroxide (H2O2), House dust mites (HDM), Adenosine triphosphate (ATP), P2X purinoceptor 7 (P2X7R), Mitochondrial DNA (mtDNA), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Janus kinase-signal transducer and activator of transcription (JAK-STAT), Leucine rich Repeat and Pyrin domain containing (NLRP), Absent in melanoma 2 (AIM2), Interleukin (IL), Interferon-stimulated genes (ISG), Reactive oxygen species (ROS), Pattern recognition receptor (PRR), Gasdermin A/D (GSDMA/GSDMD).
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Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting against self-tissues plays a crucial pathogenic role. However, there is increasing evidence that inflammasomes, which are large multiprotein complexes that were first described 20 ye...
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... Long double-stranded RNA (dsRNA) generated in the course of infections of positivestrand RNA viruses, e.g., Semliki Forest virus, can bind and activate NLRP1 inflammasome in human keratinocytes [82]. NLPR1 inflammasome has been implied in prompting the onset of psoriasis, either by increasing the susceptibility to psoriasis or by dysregulated release of pro-inflammatory cytokines including IL-1β and IL-18 [83][84][85]. Very similarly, NLRP1 has the capacity to sense bacterial pathogen exotoxin, such as exotoxin A secreted by Pseudomonas aeruginosa and diphtheria toxin by Corynebacterium diphtheriae, and induce cell death and IL-1β/ IL-18 secretion [86]. ...
Psoriasis is an immune-mediated inflammatory skin disease, involving a complex interplay between genetic and environmental factors. Previous studies have demonstrated that genetic factors play a major role in the pathogenesis of psoriasis. However, non-genetic factors are also necessary to trigger the onset and recurrence of psoriasis in genetically predisposed individuals, which include infections, microbiota dysbiosis of the skin and gut, dysregulated lipid metabolism, dysregulated sex hormones, and mental illness. Psoriasis can also be induced by other environmental triggers, such as skin trauma, unhealthy lifestyles, and medications. Understanding how these triggers play a role in the onset and recurrence of psoriasis provides insights into psoriasis pathogenesis, as well as better clinical administration. In this review, we summarize the triggers for the onset and recurrence of psoriasis and update the current evidence on the underlying mechanism of how these factors elicit the disease.
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.
Inflammasomes are cytoplasmic protein complexes that play a crucial role in protecting the host against pathogenic and sterile stressors by initiating inflammation. Upon activation, these complexes directly regulate the proteolytic processing and activation of proinflammatory cytokines IL-1β and IL-18 to induce a potent inflammatory response, and inducing a programmed form of cell death called pyroptosis to expose intracellular pathogens to the surveillance of the immune system, thus perpetuating inflammation. There are various types of inflammasome complexes, with the NLRP1 inflammasome being the first one identified in 2002 and currently recognized as the predominant inflammasome sensor protein in human keratinocytes. Human NLRP1 exhibits a unique domain structure, containing both an N-terminal pyrin (PYD) domain and an effector C-terminal caspase recruitment domain (CARD). It can be activated by diverse stimuli, such as viruses, UVB radiation and ribotoxic stress responses (RSR). Specific mutations in NLRP1 or related genes have been associated with rare monogenic skin disorders, such as multiple self-healing palmoplantar carcinoma (MSPC), familial keratosis lichenoides chronica (FKLC), autoinflammation with arthritis and dyskeratosis (AIADK) and dipeptidyl peptidase 9 (DPP9) deficiency. Recent research breakthroughs have also highlighted the involvement of dysfunctions in the NLRP1 pathway in a handful of seemingly unrelated dermatological conditions. These range from monogenic autoinflammatory diseases to polygenic autoimmune diseases such as vitiligo, psoriasis, atopic dermatitis and skin cancers including squamous cell carcinoma (SCC), melanoma and Kaposi's sarcoma. Additionally, emerging evidence suggests further implications of NLRP1 in systemic lupus erythematosus (SLE), pemphigus vulgaris, Addison's disease, Papillon-Lefèvre syndrome and leprosy. The aim of this review is to shed light on the implications of pathological dysregulation of the NLRP1 inflammasome in skin diseases and investigate the potential rationale for targeting this pathway as a future therapeutic approach.
