Background/Purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent joint inflammation, cartilage destruction, and bone erosion. Among the various immune cells involved in RA pathogenesis, macrophages play a central role by mediating inflammatory responses and tissue damage. Integrins, particularly αvβ3 integrin, are critical regulators of macrophage differentiation and inflammatory signaling via the PI3K/Akt pathway and its downstream effectors, including FOXO3a and IRF7. DICAM (Mxra8), a transmembrane protein, has been identified as a negative regulator of αvβ3 integrin signaling, yet its role in RA remains unclear. This study explores the regulatory function of DICAM in macrophage differentiation and inflammation in the context of RA.

Methods: We utilized the K/BxN serum transfer mouse model of rheumatoid arthritis to evaluate whether DICAM deficiency influences cartilage destruction and macrophage infiltration in vivo. To investigate the role of DICAM in macrophage signaling in vitro, we employed THP-1-derived macrophages. In addition, we performed rescue experiments to confirm whether the regulatory effects of DICAM on macrophage differentiation and inflammatory responses were mediated, at least in part, by suppression of β3 integrin.

Results: Using a K/BxN serum transfer mouse model of RA, we demonstrate that DICAM deficiency exacerbates arthritis severity, cartilage degradation, and macrophage infiltration. In vitro experiments with THP-1-derived macrophages show that DICAM inhibits macrophage differentiation, phagocytic activity, and pro-inflammatory cytokine expression by suppressing αvβ3 integrin expression and downstream PI3K/Akt signaling. Overexpression of DICAM reduced integrin activation, FOXO3a phosphorylation, and IRF7 expression, while knockdown enhanced these processes, promoting an inflammatory macrophage phenotype. Rescue experiments further confirmed that the inhibitory effects of DICAM on macrophage differentiation and inflammatory responses are mediated, at least in part, by the suppression of β3 integrin.

Conclusion: These results, indicating DICAM’s protective role in mitigating joint pathology, highlight DICAM as a critical modulator of macrophage function in RA and a potential therapeutic target for reducing inflammation and tissue damage. This study advances our understanding of DICAM’s role in RA pathogenesis and its potential as a biomarker and therapeutic intervention.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-dicam-in-modulating-macrophage-differentiation-and-inflammatory-responses-via-%ce%b1v%ce%b23-integrin-signaling-in-rheumatoid-arthritis/