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Inflammasomes are cytosolic multi-protein platforms that sense both microbial and damage-associated molecular patterns (danger signals) and initiate a potent innate immune anti-microbial response (1) by a sensor protein and caspase-1 linked by Adaptor Protein (apoptosis-associated speck-like protein) (ASC) (4, 5). Inflammasomes recognize PAMPs, DAMPs, or homeostasis-altering molecular processes (HAMPs) (2).
Several distinct proteins (sensors) nucleate inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRC4/NAIP, AIM2, pyrin, and caspases-4/-5/-11 (3).
When the inflammasome is formed, it activates caspase-1. This enzyme not only cuts pro-interleukin (IL)-1b and pro-IL-18 to create active cytokines but also cuts a protein called gasdermin-D (GSDMD). GSDMD then makes holes in cell membranes, which causes the release of inflammatory Interleukin-1 (IL-1) / Interleukin-1 family and leads to cell death known as pyroptosis (6).
In eubiosis, inflammasomes regulate tissue repair and proliferation, microflora composition, and host-microflora interactions. The NLRP3 inflammasome in hematopoietic stem cells and the NLRP6 inflammasome in enterocytes are involved.
Dysregulation of these processes by aberrant functions of inflammasomes NLRP3 and NLRP6 leads to auto-inflammation of the gut mediated by changes in microflora, local increases in IL-18 and IL-1 beta, resulting in aberrant tissue repair and uncontrolled inflammation.
Finally, chronic inflammasome dysregulation (NLRP6, NLRP12 inflammasome, and NLRC4 in enterocytes, NLRP3 and presumably NLRP12 in stem cells, NLRP6 in myofibroblasts) can lead to inflammation-induced tumorigenesis, mediated by dysbiosis, chronically impaired tissue repair mechanisms and altered local tumor surveillance.
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see also:
Adaptor Protein (apoptosis-associated speck-like protein) (ASC)
NLRP3 Inflammasome Activation