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Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) (referred to as [Ptpn6.sup.spin] mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in [Ptpn6.sup.spin] mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1[alpha] and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in [Ptpn6.sup.spin] mice. In order to identify new kinases involved in SHP-1-mediated inflammation, we took a genetic approach and discovered apoptosis signal-regulating kinases 1 and 2 (ASK1 and ASK2) as novel kinases regulating Ptpn6-mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in [Ptpn6.sup.spin] mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in [Ptpn6.sup.spin] mice. Mechanistically, ASK regulates [Ptpn6.sup.spin]-mediated disease by controlling proinflammatory signaling in the neutrophils. Collectively, the present study identifies SHP-1 and ASK signaling crosstalk as a critical regulator of IL-1[alpha]-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans., Introduction Mutations in the PTPN6 gene that encodes for the protein tyrosine phosphatase Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) have been linked with autoinflammatory and autoimmune diseases [...]

Inflammasomes are a specialized group of intracellular sensors that are key components of the host innate immune system. Autoinflammatory diseases are disorders of the innate immune system that are characterized by recurrent inflammation and serious complications. Dysregulation of the inflammasome is associated with the onset and progression of several autoinflammatory and autoimmune diseases, including cryopyrin‐associated periodic fever syndrome, familial Mediterranean fever, rheumatoid arthritis, and systemic lupus erythematosus. In this review, we discuss the involvement of various inflammasome components in the regulation of autoinflammatory disorders and describe the manifestations of these autoinflammatory diseases caused by inflammasome activation. [ABSTRACT FROM AUTHOR]

Summary: Dysregulated inflammation is one of the hallmarks of cancer initiation and progression. Emerging evidence indicates that inflammasomes play a central role in regulating immune cell functions in various infections and cancer. Inflammasomes are multimeric complexes consisting of nucleotide‐binding oligomerization domain (NOD) ‐like receptors (NLRs). Among the NLRs, NOD1, NOD2 and NLRP3 respond to a variety of endogenous (i.e. damage‐associated molecular patterns) and exogenous (i.e. pathogen‐associated molecular patterns) stimuli. The NLRP3 inflammasome is associated with the onset and progression of autoinflammatory and autoimmune diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, and cryopyrin‐associated periodic fever syndrome. NLRP3 is also associated with a wide variety of infections and tumorigenesis that are closely correlated with chemotherapy response and prognosis. In this review, we explore the rapidly expanding body of research on the expression and functions of NLRP3 in infections and cancers and outline novel inhibitors targeting the NLRP3 inflammasome that could be developed as therapeutic alternatives to current anticancer treatment. "The NLRP3 inflammasome is important not only for fighting against bacterial, fungal and viral infections but also for mediating cancer initiation and progression. NLRP3 inflammasome activation can create a pro‐inflammatory microenvironment that induces malignant transformation and suppresses local immunity normally provided by natural killer or T cells. In this review, we summarize and discuss the current understanding of the role of NLRP3 inflammasome in infections and cancer". [ABSTRACT FROM AUTHOR]