CD300f:IL-5 cross-talk inhibits adipose tissue eosinophil homing and subsequent IL-4 production

Abstract

Eosinophils and their associated cytokines IL-4 and IL-5 are emerging as central orchestrators of the immune-metabolic axis. Herein, we demonstrate that cross-talk between the Ig-superfamily receptor CD300f and IL-5 is a key checkpoint that modifies the ability of eosinophils to regulate metabolic outcomes. Generation of Il5 Tg /Cd300f −/− mice revealed marked and distinct increases in eosinophil levels and their production of IL-4 in the white and brown adipose tissues. Consequently, Il5 Tg /Cd300f −/− mice had increased alternatively activated macrophage accumulation in the adipose tissue. Cd300f −/− mice displayed age-related accumulation of eosinophils and macrophages in the adipose tissue and decreased adipose tissue weight, which was associated with decreased diet-induced weight gain and insulin resistance. Notably, Il5 Tg /CD300f −/− were protected from diet-induced weight gain and glucose intolerance. These findings highlight the cross-talk between IL-5 receptor and CD300f as a novel pathway regulating adipose tissue eosinophils and offer new entry points for therapeutic intervention for obesity and its complications.

CD300 family receptors regulate eosinophil survival, chemotaxis, and effector functions

“…It is important to note that at least in mice, contradicting data exists regarding the expression pattern of CD300f. We have recently shown that baseline tissue expression of CD300f (at least in the colon and adipose tissue) is nearly exclusively confined to eosinophils as other tissue resident cells such as macrophages, DCs and mast cells barely express CD300f . In contrast to our findings, other groups have reported that CD300f in the colon is expressed by mast cells, macrophages and DCs .…”

“…Furthermore, baseline expression of CD300f was decreased in BM eosinophils from Il5 −/− mice. Although IL‐5 regulated the expression of CD300f, CD300f deficiency did not alter eosinophil numbers in vivo . It is noteworthy that IL‐5 is capable of regulating the expression of additional Ig‐superfamily receptors with inhibitory/activation capabilities.…”

“…However, as eosinophils mature in the BM (and become Siglec‐F + /CCR3 + ), the expression of CD300f is increased and is maintained in peripheral blood and peritoneal eosinophils. Mouse colonic and adipose tissue eosinophils expressed markedly elevated levels of CD300f in comparison with eosinophils from the BM and blood . It is important to note that at least in mice, contradicting data exists regarding the expression pattern of CD300f.…”

“…Remarkably, Il5 Tg /Cd300f −/− mice displayed increased IL‐4 expression in the adipose tissue, which resulted with increased proliferation of monocytes and macrophages and augmented differentiation into an alternatively activated phenotype, as assessed by various markers such as arginase 1. Subsequently, Il5Tg/Cd300f −/− were protected from diet‐induced weight gain and glucose intolerance to a larger extent than Il5Tg/Cd300f +/+ mice . Thus, CD300f is a negative regulator of IL‐5‐induced eosinophil accumulation and IL‐4 production in the adipose tissue.…”

“…Furthermore, generation of Il‐5 Tg /Cd300f −/− mice resulted in specific and marked recruitment of eosinophils (and macrophages) into the white and brown adipose tissue and significantly elevated of IL‐4 expression in eosinophils (Fig. ) …”