Diverging inflammasome signals in tumorigenesis and potential targeting

Abstract

Inflammasomes are molecular platforms that assemble upon sensing various intracellular stimuli. Inflammasome assembly leads to activation of caspase-1, thereby promoting the secretion of bioactive interleukin-1β and interleukin-18 and inducing an inflammatory cell death called pyroptosis. Effectors of the inflammasome efficiently drive an immune response, primarily providing protection against microbial infections and mediating control over sterile insults. However, aberrant inflammasome signaling is associated with pathogenesis of inflammatory and metabolic diseases, neurodegeneration, and malignancies. Chronic inflammation perpetuated by inflammasome activation plays a central role in all stages of tumorigenesis, including immunosuppression, proliferation, angiogenesis, and metastasis. Conversely, inflammasome signaling also contributes to tumor suppression by maintaining intestinal barrier integrity, which portrays the diverse roles of inflammasomes in tumorigenesis. Studies have underscored the significance of environmental factors, such as diet and gut microbiota [G] in inflammasome signaling, which in turn influences tumorigenesis. In this review, we deliver an overview of the interplay between inflammasomes and tumorigenesis and discuss their potential as a therapeutic target. ToC blurb Inflammasome signaling in myeloid cells largely protects against microbial infections. Aberrant inflammasome signaling promotes chronic inflammation, which contributes to tumorigenesis. This Review presents an overview of the diverging roles of inflammasomes in cancer and discuss its targeting potential in anti-cancer therapy.

Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity–independent pyroptosis, apoptosis, necroptosis, and inflammatory disease

“…The NLRP3 inflammasome is one of the most studied inflammasomes; it is activated in response to a wide array of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns. Conventional activation of the NLRP3 inflammasome requires two signals: a priming signal often provided through TLRs and an activation signal provided by molecules such as ATP, nigericin, alum, silica, or pore-forming toxins (Karki and Kanneganti, 2019). Although inflammasome activation is critical for protection against infection, this system comes with the cost of a potential predisposition to unwanted inflammatory diseases through excessive inflammasome activation.…”

Toward targeting inflammasomes: insights into their regulation and activation

“…[14][15][16][17][18] Additionally, chronic inflammasome activation has been tied to the development of metabolic syndromes, neurodegenerative diseases, and cancer progression. [19][20][21] It is therefore unsurprising that inflammasome activation is a tightly regulated process. A number of transcription factors have been found to regulate the expression of inflammasome components, downstream effector molecules, and the upstream regulatory molecules required for successful activation.…”

NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

“…Inflammasome complexes function as crucial intracellular effectors to initiate innate immunity and thus to defend against infections or tissue damage [22,23]. It has been demonstrated that nucleotide-binding leucine-rich repeat containing receptor (NLR) family pyrin domaincontaining 3 (NLRP3) and NLR family CARD domaincontaining protein 4 (NLRC4) can both can form multiprotein complexes called inflammasomes, to activate CASP1, which subsequently cleaves the pore-forming protein GSDMD [15,24,25]. Previous studies have shown that the recently discovered NLR family pyrin domain-containing 12 (NLRP12) plays an important role in regulating the gut microbiota and autoinflammatory disease [26,27].…”