Background/Purpose: Monocytes are critical to rheumatoid arthritis (RA) disease pathogenesis and are recruited to the inflamed synovium by inflammation-driven chemokines.  G protein signaling modulator 3 (GPSM3) is a newly discovered member of the novel family of GoLoco motif proteins known to regulate G protein heterotrimer assembly and function, a mechanism by which chemokine receptors signal.  GPSM3 is selectively expressed in monocytes and may regulate monocyte function through chemokine G protein coupled receptor (GPCR) interactions, which in turn may affect inflammatory arthritis disease expression.

Methods:

• GPSM3-deficient monocytic cells were generated from the parental THP-1 cell line and a GPSM3-deficient mouse was created.
• A monoclonal antibody to GPSM3 (mAb 35.5.1) was developed and GPSM3 expression was analyzed by immunoblotting lysates from hematopoietic lineage-derived human cell lines.
• Migration studies of Ly6C+ splenocytes were conducted using Transwell inserts (5 µm pore size) and analyzed for chemotaxis by flow cytometry.
• Monocytic subsets in the spleen were enumerated using multicolor flow cytometry.
• Collagen Antibody Induced Arthritis (CAIA) was induced using the 5 clone Chondrex antibody cocktail and LPS booster on GMSM3-/- and wild type mice per manufacturer’s instructions.
• The levels of various intra-articular proinflammatory chemokine receptors and cytokines known to be important to RA and CIA disease pathogenesis were evaluated by quantitative PCR.  

Results: GPSM3 expression is predominantly restricted to the monocytic lineage and modulated during monocyte differentiation.  Data with GPSM3-deficient mice show that CAIA is blunted clinically and histopathologically with specifically reduced intra-articular IL-6,IL-1β, CCR2,and CX3CR1 expression.  Ex vivo results show a GPSM3-dependent decrease in ligand-specific migration of Ly6C+ CD11b+ spenocytes to the proinflammatory monocyte chemokines CCL2, CX3CL1, and chemerin.  

Conclusion: Proinflammatory functions of monocytes critical to RA development are reliant on GPSM3 function. Having a single protein target for RA therapeutic intervention that appears to selectively affect proinflammatory monocyte infiltration into the joint represents a paradigm shift from previous therapeutic attempts at single cytokine or chemokine neutralization.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/g-protein-signaling-modulator-3-is-a-key-regulator-of-monocyte-driven-inflammatory-arthritis/