MEK5/ERK5 signaling mediates IL-4-induced M2 macrophage differentiation through regulation of c-Myc expression

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Luiz, Joao Paulo M. ; Toller-Kawahisa, Juliana E. ; Viacava, Paula R. ; Nascimento, Daniele C. ; Pereira, Priscilla T. ; Saraiva, Andre L. ; Prado, Douglas S. ; Le Bert, Marc ; Giurisato, Emanuele ; Tournier, Cathy ; Cunha, Thiago M. ; Cunha, Fernando Q. ; Quesniaux, Valerie ; Ryffel, Bernhard ; Alves-Filho, Jose C.

• Document type: Journal article
• Source: Journal of Leukocyte Biology; v. 108, n. 4, p. 9-pg., 2020-08-03.

Abstract

Macrophages are highly plastic cells, responding to diverse environmental stimuli to acquire different functional phenotypes. Signaling through MAPKs has been reported to regulate the differentiation of macrophages, but the role of ERK5 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. Pharmacologic inhibition of MEK5, an upstream activator of ERK5, markedly reduced the expression of classical M2 markers, such asArg-1,Ym-1, andFizz-1, as well as the production of M2-related chemokines and cytokines, CCL22, CCL17, and IGF-1 in IL-4-stimulated macrophages. Moreover, pharmacologic inhibition of ERK5 also decreased the expression of several M2 markers induced by IL-4. In accordance, myeloid cell-specificErk5depletion (Erk5 (increment mye)), usingLysM(cre)/Erk5(f/f)mice, confirmed the involvement of ERK5 in IL-4-induced M2 polarization. Mechanistically, the inhibition of ERK5 did not affect STAT3 or STAT6 phosphorylation, suggesting that ERK5 signaling regulates M2 differentiation in a STAT3 and STAT6-independent manner. However, genetic deficiency or pharmacologic inhibition of the MEK5/ERK5 pathway reduced the expression of c-Myc in IL-4-activated macrophages, which is a critical transcription factor involved in M2 differentiation. Our study thus suggests that the MEK5/ERK5 signaling pathway is crucial in IL-4-induced M2 macrophage differentiation through the induction of c-Myc expression. (AU)

• FAPESP's process: 16/05377-3 - Role of Erk5 pathway on Th17 and Treg cells differentiation and on experimental autoimmune encephalomyelitis
• Grantee: Douglas da Silva Prado
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/20692-5 - Regulation and function of O-GlcNAcylation in TAM macrophage differentiation and tumor progression
• Grantee: João Paulo Mesquita Luiz
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/01714-8 - PKM2 contribution to neutrophils' activation in experimental systemic lupus erythematosus onset
• Grantee: Juliana Escher Toller
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/12671-1 - The role of succinate and its receptor GPR91 on the pathophysiology of experimental arthritis
• Grantee: André Luis Lopes Saraiva
• Support Opportunities: Scholarships in Brazil - Doctorate