Bone marrow–derived macrophages (BMDMs) were stimulated for 16 hours with either LPS/IFN-γ or IL-4 to promote M1- or M2-like macrophages (MΦs), respectively. (A) iRhom2-mutant cells had increased M1 gene expression (Fcgr1 and Cd86) when stimulated with LPS/IFN-γ compared with controls, and reduced inhibition (Cd80) with IL-4 antiinflammatory stimulation. (B) Stimulation of iRhom2-deficient (iRhom2–/–) BMDMs with IL-4 activated M2 gene expression (Cd206 and Arg1) to a significantly greater extent than in wild-type controls. (C) iRhom2-mutant cells had increased M1 cytokines when treated with proinflammatory stimulation LPS/IFN-γ similar to controls, but relatively increased TNF-α expression with IL-4 stimulation. (D) iRhom2–/– MΦs revealed similar induction of TGF-β1, and increased IL-10, under proinflammatory (LPS/IFN-γ) conditions, compared with control cells. Data are shown as the mean ± SEM, n = 3 for each experimental group. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, 1-way ANOVA and post-hoc test.