IL-10 enhances the phenotype of M2 macrophages induced by IL-4 and confers the ability to increase eosinophil migration

Abstract

M2 macrophages have been subdivided into subtypes such as IL-4-induced M2a and IL-10-induced M2c in vitro. Although it was reported that IL-10 stimulation leads to an increase in IL-4Rα, the effect of IL-4 and IL-10 in combination with macrophage subtype differentiation remains unclear. Thus, we sought to clarify whether IL-10 enhanced the M2 phenotype induced by IL-4. In this study, we showed that IL-10 enhanced IL-4Rα expression in M-CSF-induced bone marrow-derived macrophages (BMDMs). Global gene expression analysis of M2 macrophages induced by IL-4, IL-10 or IL-4 + IL-10 showed that IL-10 enhanced gene expression of M2a markers induced by IL-4 in M-CSF-induced BMDMs. Moreover, IL-4 and IL-10 synergistically induced CCL24 (Eotaxin-2) production. Enhanced CCL24 expression was also observed in GM-CSF-induced BMDMs and zymosan-elicited, thioglycolate-elicited and naive peritoneal macrophages. CCL24 is a CCR3 agonist and an eosinophil chemoattractant. In vitro, IL-4 + IL-10-stimulated macrophages produced a large amount of CCL24 and increased eosinophil migration, which was inhibited by anti-CCL24 antibody. We also showed that IL-4 + IL-10-stimulated (but not IL-4 or IL-10 alone) macrophages transferred into the peritoneum of C57BL/6J mice increased eosinophil infiltration into the peritoneal cavity. These results demonstrate that IL-4 + IL-10-simulated macrophages have enhanced M2a macrophage-related gene expression, CCL24 production and eosinophil infiltration-inducing activity, thereby suggesting their contribution to eosinophil-related diseases.

NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury

“…IL-10 regulates TLR signaling [47], and IL-10 deficient mice exhibit exaggerated responses to LPS [48]. IL-10 can also enhance anti-inflammatory activation induced by IL-4 [7]. Here, we show that LPS/IL-4 stimulation enhances IL-10 release, an effect which is robustly increased in NOX2 −/− BMDMs.…”

“…Stimulation of macrophages with interleukin-4 (IL-4) upregulates the expression of markers of the anti-inflammatory phenotype—effects mediated in part through activation of STAT6 [6]. Other inflammatory mediators such as interleukin-10 (IL-10) [7] and insulin-stimulating growth factor-1 (IGF-1) [8] may also activate the anti-inflammatory phenotype.…”

The Atypical Inhibitor of NF-κB, IκBζ, Controls Macrophage Interleukin-10 Expression

“…Our results, however, indicate that decreased IL-10 expression contributes to at least some of the features of M1 polarization in Nfkbiz Ϫ/Ϫ mice. In line, IL-10-producing monocytes have been found to preferentially differentiate to M2 macrophages (45,46). Dysregulation of Il10 expression has been linked to several immune disorders.…”

Macrophage polarization in response to epigenetic modifiers during infection and inflammation

“…Specifically, these macrophages release tumor necrosis factor α (TNFα), IL1, IL6, and reactive oxygen intermediates, and are recognized as M1 macrophages [35]. By contrast, the macrophages that release IL4 trigger the expression of anti-inflammatory cytokines, such as Arginase-1 (Arg1) and IL10, as well as increasing the expression of cell surface receptor CD206 [36]. These macrophages are found to inhibit activated macrophages (M1) and are known as M2 macrophages [37].…”