Granulocyte-macrophage colony stimulating factor (GM-CSF) has emerged as a major proinflammatory cytokine and targeting GM-CSF has been successful in early phase clinical trials for Rheumatoid Arthritis (RA). However, little is known about where GM-CSF comes from during inflammatory pathology, especially in the context of autoimmunity, and how GM-CSF receptor signaling is controlled after activation. This is particularly relevant in RA, where autoantibodies (e.g. anti-cyclic citrullinated peptide antibodies) correlate with more severe disease. Using the K/BxN serum transfer induced arthritis (STIA) model and comprehensive functional studies (including two novel transgenic mouse strains, disease therapy models, surface plasmon resonance, RNASeq, and proteomics), we report two major findings: (1) tissue NK cells may amplify joint inflammation in arthritis via GM-CSF production and thus represent a novel target in immune complex-mediated pathology, and (2) the SOCS family member CIS is a direct, stimulus-induced negative regulator of GM-CSF receptor (GM-CSFR) signaling in myeloid cells during inflammation. These data support the idea of novel therapeutic strategies, such as CIS mimetics, to boost intracellular stores of CIS in inflammatory cells and suppress GM-CSF-driven inflammation. A CIS mimetic may also be applicable to limit the effects of IL-3 in sepsis and IL-5 in allergic inflammation. These findings may also have implications for cancer immunotherapy approaches such as CIS-inhibitors already aimed at increasing JAK/STAT signaling in NK cells and CD8 T cells, and enhancing their anti-tumor functions. Inhibition of CIS as a cancer treatment would presumably also increase GM-CSF signaling in myeloid cells and potentially skew tumor-resident myeloid/dendritic cell development and differentiation, which may impact on tumor antigen presentation and myeloid-derived suppressor cell (MDSC) differentiation.