IL‐34‐ and M‐CSF‐induced macrophages switch memory T cells into Th17 cells via membrane IL‐1α

Abstract

Macrophages orchestrate the immune response via the polarization of CD4+ T helper GM-CSF macrophages promote Th1 cells. The polarization of memory T cells into Th17 cells is mediated via membrane IL-1α (mIL-1α), which is constitutively expressed by M-CSF-, IL-34 macrophages, andTAMs. This study elucidates a new mechanism that allows macrophages to maintain locally restrained and smoldering inflammation, which is required in angiogenesis and metastasis.Keywords: IL-34 r IL-1α r Inflammation r Macrophages r M-CSF r Th17 cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacrophages have a central role in numerous physiological processes, such as control of infection, wound healing, inflammation, and tissue homeostasis. Tissues-resident macrophages (such as Correspondence: Dr. Pascale Jeannin e-mail: pascale.jeannin@univ-angers.fr microglia, Kupffer cells, and osteoclasts) are found in connective tissues and in every organ in the body [1]. Moreover, upon danger signals, monocytes are rapidly recruited and differentiate into macrophages [1]. Cells of the monocyte-macrophage lineage are characterized by remarkable plasticity and diversity * These authors contributed equally to this work. In human, three cytokines, GM-CSF, M-CSF, and IL-34, promote monocyte survival and differentiation into macrophages [4]. Macrophages generated in the presence of GM-CSF (GM-CSF macrophages) produce IL-12, IL-23, and proinflammatory cytokines, but low levels of . They exhibit T-cell costimulatory, antitumoral, and microbicidal properties [2]. GM-CSF macrophages are usually referred to as M1 cells (even in the absence of IFN-gamma stimulation). IL-34 and M-CSF, which signal via the M-CSF receptor (c-fms or CD115), induce the differentiation of human monocytes into macrophages with closely similar phenotypes [6]. These macrophage subsets are IL-10 high low cells that do not produce IL-23 and express low levels of CD80, and CD86 [6,7]. M-CSF-and IL-34 macrophages exhibit low T-cell costimulatory properties and dampen the activity of effector T cells [6,7]. In solid tumors, tumor-associated macrophages (TAMs) are the most abundant immunosuppressive leukocytes in the tumor microenvironment and, in numerous cancers, their density is correlated with a poor prognosis [3]. In addition to immunoregulatory properties, TAMs favor angiogenesis and promote tumorcell progression and metastasis [3]. In previous studies, we have shown that + Treg cells, have been described [14,17]. As we suspected that M-CSF-and IL-34 macrophages should favor the switch of memory T cells into Treg cells, we analyzed the expression of some Treg-associated markers by Th17 cells generated in the presence of M-CSF-and IL-34 macrophages. These Th17 cells expressed CCR4, CCR6, and CD161, but not TGF-β, CD39, CD73, IL-10, and FoxP3 (Table 1 and Supporting Information Fig. 2). In contrast, these cells express the mRNA encoding CCR6 (Fig. 2B) and IL-21 (Fig. 2C), two markers of conventional Th...

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