• Bhesh Raj Sharma and Thirumala-Devi Kanneganti.
• Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee.
• Transl Res. 2023 Feb 1; 252: 455245-52.

AbstractColorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the world. Inflammation is often an underlying risk factor for developing CRC. Maintaining gut homeostasis and balancing inflammation is therefore critical to prevent CRC development. One key class of molecular complexes that impact gut homeostasis are inflammasomes, cytosolic multiprotein immune complexes that assemble upon sensing various intracellular alterations. Inflammasomes regulate inflammation, cell death, cytokine release, signaling cascades, and other cellular processes. Roles for inflammasomes in colitis and colitis-associated CRC have been shown in multiple animal models. The activation of inflammasomes leads to the release of the bioactive forms of interleukin (IL)-1β and IL-18, the inflammasome effector cytokines. These cytokines ensure an optimal inflammatory immune response during colitis and colitis-associated CRC. The activation of some inflammasome sensors, including NLRP3, NLRP1, NLRP6, and Pyrin, provides protection from colitis-associated CRC via effector cytokine-dependent mechanisms. Additionally, activation of other inflammasome sensors, such as AIM2, NLRC4, and NAIPs, provides mostly effector cytokine-independent protection. Inflammasomes can also act as integral components of PANoptosomes, which are multifaceted complexes that integrate components from other cell death pathways and regulate a unique form of innate immune inflammatory cell death called PANoptosis. Furthermore, IRF1, a key regulator of some inflammasomes and PANoptosomes, has been implicated in CRC. It is therefore critical to consider the role of inflammasomes in effector cytokine-dependent and -independent protection as well as their role in PANoptosis to modulate CRC for therapeutic targeting. Here, we discuss the mechanisms of inflammasome activation, the functions of inflammasomes in CRC, and current obstacles and future perspectives in inflammasome and CRC research.Copyright © 2022 Elsevier Inc. All rights reserved.

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