Abstract

Clinical observations reveal that Mek-Erk inhibitors exert paradoxical immunoregulatory effects on macrophages, yet the mechanisms governing the pathway’s specific immunoregulatory outputs remain elusive. Here, we identify Ets1 as a discriminative effector that couples Mek-Erk signaling specifically to anti-inflammatory polarization. We show that while various stimuli activate Erk, only the anti-inflammatory IL-4 activates the transcriptional activity of Ets1 in a Thr38 (T38) phosphorylation-dependent manner. Functionally, myeloid-specific Ets1 knockout mice exhibited exacerbated adipose inflammation and metabolic dysfunction under both physiological and obesity conditions. Mechanistically, Ets1 raises Irf4 expression level via both transcriptional regulation and chromatin remodeling, thereby inducing macrophage anti-inflammatory polarization. Taken together, we demonstrate that Ets1 serves as a critical discriminator activated specifically by IL-4 stimulation but remaining inactive under pro-inflammatory conditions. This bifurcated activation enables Erk signaling to differentially engage downstream effectors based on upstream stimuli, thereby directing macrophage functional specialization.