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

Autor: André L. L. Saraiva, Emanuele Giurisato, Thiago M. Cunha, Marc LeBert, Priscilla Aparecida Tartari Pereira, Cathy Tournier, Douglas Silva Prado, Paula Ramos Viacava, Daniele C. Nascimento, Juliana E Toller-Kawahisa, João Paulo Mesquita Luiz, Fernando Q. Cunha, Bernhard Ryffel, José C. Alves-Filho, Valérie F. J. Quesniaux
Přispěvatelé: Universidade de São Paulo (USP), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), University of Manchester [Manchester]
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
STAT3 Transcription Factor
Chemokine
MAP Kinase Signaling System
Immunology
Macrophage polarization
[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
MAP Kinase Kinase 5
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Mice
0302 clinical medicine
Immunology and Allergy
Animals
M2 macrophages
STAT3
IMUNOLOGIA
Transcription factor
MEK5
Interleukin 4
Mitogen-Activated Protein Kinase 7
Mice
Knockout
Mice
Inbred BALB C
Manchester Cancer Research Centre
biology
ResearchInstitutes_Networks_Beacons/mcrc
Macrophages
IL-4
Cell Differentiation
Cell Biology
M2 Macrophage
Antigens
Differentiation
Cell biology
030104 developmental biology
ERK5
Gene Expression Regulation
030220 oncology & carcinogenesis
biology.protein
Phosphorylation
Interleukin-4
STAT6 Transcription Factor
CCL22
Zdroj: Journal of Leukocyte Biology
Journal of Leukocyte Biology, Society for Leukocyte Biology, 2020, 108 (4), pp.1215-1223. ⟨10.1002/JLB.1MA0520-016R⟩
Tournier, C 2020, ' MEK5/ERK5 signaling mediates IL-4-induced M2 macrophage differentiation through regulation of c-Myc expression ', Journal of leukocyte biology|J Leukoc Biol . https://doi.org/10.1002/JLB.1MA0520-016R
Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
ISSN: 0741-5400
DOI: 10.1002/JLB.1MA0520-016R⟩
Popis: 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.
Databáze: OpenAIRE
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