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TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3[epsilon] as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3[epsilon] was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3[epsilon] resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3[epsilon] signaled through PI3K/Akt/mTOR to restrict NF-[kappa]B activation while simultaneously stimulating C/EBP[beta] activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3[epsilon] as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3[epsilon] antiinflammatory pathway., Introduction Rheumatoid arthritis (RA) is a common chronic autoimmune condition characterized by inflammatory joint disease (1), resulting from protracted inflammation of the synovial membrane. Macrophages are a major subset of [...]