ASC plays a role in the priming phase of the immune response to type II collagen in collagen-induced arthritis

Abstract

Although rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, the role of IL-1β and IL-18 in the pathophysiology of RA has been well established. IL-1β and IL-18 are generated via cleavage of their pro-forms in the presence of the apoptosis-associated speck-like protein containing a caspase recruit domain (ASC), a known adaptor protein that activates procaspase-1. As such, we investigated the involvement of ASC in the progression of murine collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) using ASC-deficient (ASC(-/-)) and wild-type (ASC(+/+)) mice. Analyses were performed by immunohistochemistry for tissues and ELISA for sera. We observed an increase in the expression of ASC, as well as IL-1β and IL-18, in the joints of CIA DBA mice, which indicated that ASC is involved in disease development. Next, we demonstrated that the infiltration of inflammatory cells and cartilage/bone destruction in CIA knee joints were significantly increased in ASC(+/+) mice compared with ASC(-/-) mice. No such differences were noted in ASC(+/+) and ASC(-/-) CAIA mice. In terms of cytokine expression in knee joints, IL-1β and IL-18 were depressed in ASC-deficient CIA mice compared with wild-type mice, but were similarly expressed in CAIA joints in both mice groups. Taken together, we can conclude that ASC is involved in the development of CIA and plays a role in the priming phase of the immune response to type II collagen.

How to Use SNP_TATA_Comparator to Find a Significant Change in Gene Expression Caused by the Regulatory SNP of This Gene’s Promoter via a Change in Affinity of the TATA-Binding Protein for This Promoter

“…Because the known SNP marker rs1143627 and the unannotated SNP rs549858786 have opposite effects (relative to each other) on IL1B expression, we performed an additional keyword search for [ 54 , 63 ] “interleukin 1 β deficiency” as a biochemical marker relevant to medicine in the NCBI databases [ 4 ]. The result is shown in Table 1 and represents experimental findings [ 76 ] in a murine model of human rheumatoid arthritis, which showed an association of the interleukin 1 β deficiency with a high risk of this autoimmune disease. Within the framework of this animal model of the human disease [ 76 ], we propose rs549858786 as a candidate SNP marker of an increased risk of rheumatoid arthritis.…”

G Protein Signaling Modulator-3 Inhibits the Inflammasome Activity of NLRP3

“…This pro-inflammatory effect is thought to be medi- ated by the influence of GPSM3 on monocyte apoptosis and chemotaxis in response to several G protein-coupled receptor activating chemokines (16). This proinflammatory role of GPSM3 does not contradict the negative regulation of the NLRP3 inflammasome that we now describe because induction of collagen antibody-induced arthritis has previously been shown as independent of NLRP3 inflammasome activation (45,46). Our current data suggest that GPSM3 has pleiotropic effects on immune signaling pathways and that, in addition to modulation of G protein-coupled receptor signaling, it is also able to regulate NLRP3 inflammasome activation.…”

Inflammasomes link vascular disease with neuroinflammation and brain disorders

“…ASC À/À mice showed decreased infiltration of inflammatory cells and cartilage/bone destruction in a collagen-induced arthritis model. 165 In an Ag-induced arthritis (AIA) model, ASC À/À mice have decreased synovial IL-1b and serum amyloid A levels. In contrast, NLRP3 À/À , NLRC4 À/À or caspase-1 À/À mice do not show any alteration of joint inflammation compared with controls indicating that the effect of ASC is independent of NLRP3 or NLRC4 inflammasomes.…”