IL-33–Stimulated Murine Mast Cells Polarize Alternatively Activated Macrophages, Which Suppress T Cells That Mediate Experimental Autoimmune Encephalomyelitis

Abstract

IL-33 is known to promote type 2 immune responses through ST2, a component of the IL-33R complex, expressed primarily on mast cells, Th2 cells, group 2 innate lymphoid cells and regulatory T cells, and to a lesser extent, on NK cells and Th1 cells. Consistent with previous studies, we found that IL-33 polarized alternatively activated macrophages (AAMF) in vivo. However, in vitro stimulation of murine bone marrow-derived or peritoneal macrophages with IL-33 failed to promote arginase activity or expression of YM-1 or Retnla, markers of AAMF. Furthermore, macrophages have low/no basal expression of ST2. This suggested that alternative activation of macrophages may involve an IL-33-responsive third-party cell. Because mast cells have the highest expression of ST2 relative to other leukocytes, we focused on this cell type. Coculture experiments showed that IL-33stimulated mast cells polarized AAMF through production of soluble factors. IL-33-stimulated mast cells produced a range of cytokines, including IL-6 and IL-13. Mast cell-derived IL-13 was required for induction of AAMF, whereas mast cell-derived IL-6 enhanced macrophage responsiveness to IL-13 via upregulation of the IL-4Ra receptor. Furthermore, we found that AAMF polarized by IL-33-stimulated mast cells could suppress proliferation and IL-17 and IFN-g production by T cells. Finally, we show that AAMF polarized by IL-33-stimulated mast cells attenuated the encephalitogenic function of T cells in the experimental autoimmune encephalomyelitis model. Our findings reveal that IL-33 can promote immunosuppressive responses by polarizing AAMF via mast cell-derived IL-6 and IL-13.

Macrophage regulation & function in helminth infection

“…Further macrophage-derived pro-inflammatory cytokines with suppressive effects on type 2 immunity include IL-6 and IL-1b [125,126], although mast cell-derived IL-6 has been implicated in AAM activation by upregulating IL4Ra on macrophages [127]. Surprisingly, TNFa has been described to promote anti-helminth immunity [128] despite suppressive effects on AAM differentiation [129].…”

The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease

“…Leptin mutant ob/ob mice showed decreased percentage of mast cells in inguinal adipose tissue, but did not show mast cell deficiencies in other tissues (76). Several studies have proposed a role for mast cells in polarization of macrophages by secretion of cytokines (77). For example, IL-33 treatment of mast cells causes production of IL-6 and IL-13, which are cytokines known to promote alternatively activated macrophages that suppresses T cell inflammation (77).…”

“…Several studies have proposed a role for mast cells in polarization of macrophages by secretion of cytokines (77). For example, IL-33 treatment of mast cells causes production of IL-6 and IL-13, which are cytokines known to promote alternatively activated macrophages that suppresses T cell inflammation (77). One group has investigated the role of leptin in mast cell function and the subsequent effect on macrophages in the context of obesity (43).…”

Two Sides of the Coin: Mast Cells as a Key Regulator of Allergy and Acute/Chronic Inflammation

“…Accordingly, AAMF has immunosuppressive and anti-inflammatory effects. Notably, IL-6, another cytokine secreted by MCs, can upregulate the IL-4ra in IL-13R, which further enhances the alternating activation of macrophages [ 136 ]. Besides, in a study of autoimmune diabetes, MCs were found to play a protective role by inducing Foxp3 + Treg cells and reducing tissue inflammation [ 137 ].…”