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Abstract Number: 1663

G Protein Signaling Modulator 3 Is a Key Regulator of Monocyte-Driven Inflammatory Arthritis

Matthew J. Billard1, Patrick M. Giguére2, Brian Buckley2, Marcus W. McGinnis1, Roman Timoshchenko1, Peng Liu1, David P. Siderovski2 and Teresa K. Tarrant3, 1Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 2Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 3Medicine/Rheumatology, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: chemokines, inflammatory arthritis, monocytes and signal transduction

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Session Information

Title: Cytokines, Mediators, and Gene Regulation II

Session Type: Abstract Submissions (ACR)

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.


Disclosure:

M. J. Billard,
None;

P. M. Giguére,
None;

B. Buckley,
None;

M. W. McGinnis,
None;

R. Timoshchenko,
None;

P. Liu,
None;

D. P. Siderovski,
None;

T. K. Tarrant,
None.

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