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International audience; Macrophages play a critical role in the regulation of immune responses. They are highly plastic cells, responding to diverse environmental stimuli to acquire different functional phenotypes. Intracellular signaling through mitogen-activated protein kinases (MAPKs) has been reported to regulate the differentiation of macrophages, but the role of the atypical MAPK ERK5 signaling in IL-4-mediated M2 macrophage differentiation is still unclear. Here, we showed that the ERK5 signaling pathway plays a critical role in IL-4-induced M2 macrophage differentiation. We found that pharmacological inhibition of MEK5, an immediate upstream activator of ERK5, with BIX markedly reduced the expression of classical M2 markers, such as Arg-1, Ym-1, and Fizz-1, as well as the production of M2-related chemokines and cytokines, CCL22, CCL17 and IGF-1 in IL-4-stimulated macrophages. Moreover, pharmacological inhibition of ERK5 with XMD8-92 also decreased the expression of several M2 markers induced by IL-4. In accordance, myeloid cell-specific Erk5 depletion (ERK5 ∆mye), using LysM cre /Erk5 f/f mice, confirmed the involvement of ERK5 signaling in IL-4-induced M2 polarization. Mechanistically, we found that pharmacological inhibition of ERK5 did not affect STAT6 phosphorylation, suggesting that ERK5 signaling regulates M2 differentiation in a STAT6-independent manner. However, we found that genetic deficiency or pharmacological inhibition of the MEK5/ERK5 pathway blocked the expression of c-Myc in IL-4-activated macrophages, which is a critical transcription factor involved in M2 differentiation. Taken together, our results reveal that activation of the MEK5/ERK5 signaling pathway is crucial in IL-4-induced M2 macrophage differentiation through the induction of c-Myc expression.