Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling

Abstract

Inflammasomes contribute to colorectal cancer signaling by primarily inducing inflammation in the surrounding tumor microenvironment. Its role in inflammation is receiving increasing attention, as inflammation has a protumor effect in addition to inducing tissue damage. The inflammasome's function is complex and controlled by several layers of regulation. Epigenetic processes impact the functioning or manifestation of genes that are involved in the control of inflammasomes or the subsequent signaling cascades. Researchers have intensively studied the significance of epigenetic mechanisms in regulation, as they encompass several potential therapeutic targets. The regulatory interactions between the inflammasome and autophagy are intricate, exhibiting both advantageous and harmful consequences. The regulatory aspects between the two entities also encompass several therapeutic targets. The relationship between the activation of the inflammasome, autophagy, and epigenetic alterations in CRC is complex and involves several interrelated pathways. This article provides a brief summary of the newest studies on how epigenetics and autophagy control the inflammasome, with a special focus on their role in colorectal cancer. Based on the latest findings, we also provide an overview of the latest therapeutic ideas for this complex network.

Keywords: autophagy; colitis; colorectal cancer; epigenetics; inflammasome; regulation; therapeutic target; tumor microenvironment.

Figure 1

Classification and mode of action of various inflammasomes. There are different PAMPs that can turn on the NLRP3, NLRP1, NLRC4, AIM2, and pyrin inflammasomes. NLRP3 is also capable of detecting uric acid crystals, mtDNA, ROS, ATP, and mineral particulates (e.g., asbestos or silica), among others. AIM2 interacts structurally with particular ligands, including dsDNA. Rho modification triggers the activation of pyrins in response to toxins produced by bacteria. Upon activation, the sensors recruit and stimulate caspase-1. If an inflammasome has a CARD domain, then it can interact directly with pro-caspase-1. If it only has a pyrin domain, then it does so through the adaptor protein ASC. IL1β and IL18 are produced when pro-IL1β and pro-IL18 are cleaved and activated by caspase-1, respectively. Additionally, caspase-1 mediates the cleavage of gasdermin D to induce pyroptosis. The figure was partially created with https://www.biorender.com (accessed on 28 April 2024).

Figure 2

The NLRP3 inflammasome pathway in CRC. PAMPs and DAMPs have the ability to trigger the activation of NLRP3 inflammasomes. The activation of NFκB and subsequent overexpression of NLRP3, triggered by microbial components or endogenous cytokines, initiates the generation of pro-IL1β and pro-IL18, leading to chronic inflammation in CRC. The inflammasome is under multi-level regulation. This regulatory network includes epigenetics and autophagy machinery. The figure was partially created using https://www.biorender.com (accessed on 28 April 2024).

Figure 3

Inflammasomes and autophagy engage in cross-communication. By eliminating endogenous inflammasome activators, such as damaged mitochondria that generate reactive ROS, inflammasome components, and cytokines, autophagy can negatively regulate NLRP3 inflammasome activation. In addition to regulating the inflammatory response, autophagic machinery prevents the unusual secretion of IL1β. On the other hand, when the NLRP3 inflammasome activates, a number of distinct mechanisms govern the formation of autophagosomes. The maintenance of equilibrium between the necessary inflammatory response of the host’s defenses and the prevention of excessive inflammation require cross-communication between inflammasomes and autophagy. The figure was partly created with https://www.biorender.com (accessed on 28 April 2024).