CD300f associates with IL-4 receptor α and amplifies IL-4–induced immune cell responses

Abstract

IL-4 receptor (R) α, the common receptor chain for IL-4 and IL-13, is a critical component in IL-4-and IL-13-mediated signaling and subsequent effector functions such as those observed in type 2 inflammatory responses. Nonetheless, the existence of intrinsic pathways capable of amplifying IL-4Rα-induced responses remains unknown. In this study, we identified the myeloid-associated Ig receptor CD300f as an IL-4-induced molecule in macrophages. Subsequent analyses demonstrated that CD300f was colocalized and physically associated with IL-4Rα. Using Cd300f −/− cells and receptor cross-linking experiments, we established that CD300f amplified IL-4Rα-induced responses by augmenting IL-4/IL-13-induced signaling, mediator release, and priming. Consistently, IL-4-and aeroallergen-treated Cd300f −/− mice displayed decreased IgE production, chemokine expression, and inflammatory cell recruitment. Impaired responses in Cd300f−/− mice were not due to the inability to generate a proper Th2 response, because IL-4/IL-13 levels were markedly increased in allergen-challenged Cd300f −/− mice, a finding that is consistent with decreased cytokine consumption. Finally, CD300f expression was increased in monocytes and eosinophils obtained from allergic rhinitis patients. Collectively, our data highlight a previously unidentified role for CD300f in IL-4Rα-induced immune cell responses. These data provide new insights into the molecular mechanisms governing IL-4Rα-induced responses, and may provide new therapeutic tools to target IL-4 in allergy and asthma.IL-4 receptor | eosinophil | macrophage | CD300f | inflammation

Lipopolysaccharide-Induced CD300b Receptor Binding to Toll-like Receptor 4 Alters Signaling to Drive Cytokine Responses that Enhance Septic Shock

“…In addition to the data reported here showing CD300b regulation of TLR4 signaling, we have recently shown that CD300f associates with and regulates IL-4 receptor α-mediated responses by augmenting IL-4 and IL-13-induced signaling (Moshkovits et al, 2015). Other CD300 family members have been shown to modulate LPS-induced responses, although not through the direct recognition of LPS.…”

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

“…We have recently shown that CD300f is physically associated with IL-4Rα and that it is necessary for IL-4-induced activation of multiple cells including macrophages and eosinophils. In fact, IL-4 stimulated Cd300f −/− macrophages display decreased activation of STAT6 and subsequently decreased induction of hallmark alternatively activated markers such as Relm-α and arginase1 44 . Thus, on one hand Cd300f −/− mice display elevated eosinophilia which secrete increased levels of IL-4 and on the other hand, Cd300f −/− macrophages may be less responsive to IL-4, which may cause them to promote obesity and glucose intolerance.…”

Dendritic cells expressing immunoreceptor CD300f are critical for controlling chronic gut inflammation

“…For instance, Moshkovits et al did not detect CD300f expression on colonic macrophages or mast cells, and they failed to examine CD300f expression on DCs (34), whereas we detect CD300f expression on macrophages, DCs, neutrophils, and mast cells in colonic lamina propria (Supplemental Figure 11); similarly, Matsukawa et al (20) readily detected CD300f on the surface of colonic mast cells, macrophages, and eosinophils. The lack of detection of CD300f on lamina propria macrophages by Moshkovits and colleagues is surprising, as, in general, macrophages could be considered a hallmark of CD300f expression (18,(35)(36)(37). CD300f expression has been shown to be regulated by various cytokines (38,39), which could depend on exposure to environmental factors and/ or different microbiota communities present in the animal facilities.…”

“…The lack of detection of CD300f on lamina propria macrophages by Moshkovits and colleagues is surprising, as, in general, macrophages could be considered a hallmark of CD300f expression (18,(35)(36)(37). CD300f expression has been shown to be regulated by various cytokines (38,39), which could depend on exposure to environmental factors and/ or different microbiota communities present in the animal facilities. Although cohousing revealed that the increased sensitivity of colitis in CD300f-deficient mice was not due to differences in the gut microbiota in our experimental settings, we cannot exclude the possibility of substantial differences in the composition of gut microbiota or other environmental factors across the different animal facilities used in all 3 studies.…”