G-Protein Signaling Modulator 3 (GPSM3), a GoLoco family protein that regulates G protein coupled receptors (GPCRs), is highly expressed in immune cells, particularly monocytes. Single nucleotide polymorphisms (SNPs) at the GPSM3 gene locus that were associated with a decreased incidence of autoimmunity in humans have been shown to correlate with reduced transcript and protein expression. Furthermore, Gpsm3-/- mice fail to develop inflammatory disease in two preclinical mouse models of rheumatoid arthritis, but the underlying cellular and molecular mechanisms are currently unknown. Our published and preliminary data suggest that Gpsm3 expression levels impact monocyte survival, which could explain why Gpsm3-/- mice fail to develop inflammatory arthritis. To directly test the impact of Gpsm3 on monocyte survival ex vivo, monocytes were differentiated from the bone marrow of wild type and Gpsm3-/- mice and treated with one of four chemokines known to regulate monocyte function (Ccl2, Cx3cl1, chemerin, and Cxcl12) under apoptotic stress. Monocyte survival versus apoptosis was then measured. Preliminary results suggested that Cx3cl1, chemerin and Cxcl12 all protect against apoptosis in wild type monocytes, but fail to protect the Gpsm3-/- monocytes. Future directions involve identifying potential leukocyte subpopulations, including macrophages, which are also dependent on Gpsm3 for survival. Overall, Gpsm3 is critical to the development of monocyte inflammatory responses and could impact future development of novel therapeutic targets for the treatment of arthritis in humans.