Cytoplasmic DNA and AIM2 inflammasome in RA: where they come from and where they go?

Abstract

Rheumatoid arthritis is a chronic autoimmune disease of undetermined etiology characterized by symmetric synovitis with predominantly destructive and multiple joint inflammation. Cytoplasmic DNA sensors that recognize protein molecules that are not themselves or abnormal dsDNA fragments play an integral role in the generation and perpetuation of autoimmune diseases by activating different signaling pathways and triggering innate immune signaling pathways and host defenses. Among them, melanoma deficiency factor 2 (AIM2) recognizes damaged DNA and double-stranded DNA and binds to them to further assemble inflammasome, initiating the innate immune response and participating in the pathophysiological process of rheumatoid arthritis. In this article, we review the research progress on the source of cytoplasmic DNA, the mechanism of assembly and activation of AIM2 inflammasome, and the related roles of other cytoplasmic DNA sensors in rheumatoid arthritis.

Keywords: AIM2; cytosolic DNA; inflammasome; pyroptosis; rheumatoid arthritis.

Figure 1

Suicidal and vital NETosis processes PMA, bacteria, cytokines, etc. can all induce ‘suicidal’ NETosis, when the receptor interacts with these stimuli, Ca²⁺ is released into the cytoplasm to activate PKC, leading to the production of ROS from NOX.ROS promote neutrophil granule ROS promote disassembly of neutrophil granules, resulting in the release of enzymes such as MPO and NE into the cytoplasm and subsequently into the nucleus. MPO, NE, and PAD4 together induce CitH3 citrullination, leading to chromatin derepression, followed by disassembly of the nuclear membrane, and mixing of decondensed chromatin with proteins released from cytoplasmic granules to form NETs. The other “life-type” NETosis consists of platelets, tonicity, and other proteins released by cytoplasmic granules. NETosis is activated by platelets, complement proteins, etc. After activation of neutrophils, Ca²⁺ is transferred to the cytoplasm via SK3, and the increased concentration of Ca²⁺ in the cytoplasm causes activation of PAD4, which leads to chromatin decondensation into the cytoplasm, and then participates in CitH3 citrullination and chromatin derepression in conjunction with MPO and NE, and finally, NETs are expelled through vesicles.

Figure 2

Assembly and activation of AIM2 inflammasome Binding of dsDNA released from bacteria, viruses, or damaged mitochondria to AIM2 triggers the assembly of AIM2 inflammasome. Activated caspase-1 cleaves pro-IL-1β, pro-IL-18, and GSDMD to produce IL-1β, IL-18, and GSDMD-N. GSDMD-N inserts into the lipid structure of the cell membrane to form a plasma membrane pore, causing cellular pyroptosis. Notably, cytoplasmic bacteria activate AIM2 inflammasome via a type I interferon-dependent “non-classical” pathway, and GBPs and GTPase-mediated lysis results in the release of large amounts of bacterial dsDNA into the cytoplasm for AIM2 recognition.