CMRF35-like molecule 1 (CLM-1) regulates eosinophil homeostasis by suppressing cellular chemotaxis

Abstract

Eosinophil accumulation in health and disease is a hallmark characteristic of mucosal immunity and type 2 helper T cell (Th2) inflammation. Eotaxin-induced CCR3 (chemokine (C-C motif) receptor 3) signaling has a critical role in eosinophil chemotactic responses. Nevertheless, the expressions of immunoreceptor tyrosine-based inhibitory motif-bearing receptors such as CMRF35-like molecule-1 (CLM-1) and their ability to govern eosinophil migration are largely unknown. We now report that CLM-1 (but not CLM-8) is highly and distinctly expressed by colonic and adipose tissue eosinophils. Furthermore, Clm1⁻/⁻ mice display elevated baseline tissue eosinophilia. CLM-1 negatively regulated eotaxin-induced eosinophil responses including eosinophil chemotaxis, actin polymerization, calcium influx, and extracellular signal-regulated kinase (ERK)-1/2, but not p38 phosphorylation. Addition of CLM-1 ligand (e.g., phosphatidylserine) rendered wild-type eosinophils hypochemotactic in vitro and blockade of CLM-1/ligand interactions rendered wild-type eosinophils hyperchemotactic in vitro and in vivo in a model of allergic airway disease. Interestingly, suppression of cellular recruitment via CLM-1 was specific to eosinophils and eotaxin, as leukotriene B₄ (LTB₄)- and macrophage inflammatory protein-1α (MIP-1α)-induced eosinophil and neutrophil migration were not negatively regulated by CLM-1. Finally, peripheral blood eosinophils obtained from allergic rhinitis patients displayed elevated CLM-1/CD300f levels. These data highlight CLM-1 as a novel regulator of eosinophil homeostasis and demonstrate that eosinophil accumulation is constantly governed by CLM-1, which negatively regulates eotaxin-induced eosinophil responses.

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

“…WT eosinophils, which were pretreated with IL-4, displayed a 20-25% increase in their responsiveness to eotaxin-induced chemotaxis (Fig. 4G) (11). Consistently, Cd300f −/− eosinophils displayed increased chemotactic responses to eotaxin stimulation (Fig.…”

“…The finding that the genetic loci (human chromosome 17q22-25) of CD300 members are under strong positive evolutionary selection suggests potent immune regulatory roles for these molecules (15). Indeed, recent studies using Cd300f −/− mice revealed key roles for CD300f in governing the activation of inflammatory myeloid cells, mast cells, and eosinophils (11,12,16). However, the overall physiological function of CD300f is still largely unknown.…”

“…The only CD300 family members that possess ITIMs in their intracellular domains are CD300f and CD300a, and are thus potentially capable of suppressing immune cell activation by recruitment of phosphatases (10). Importantly, despite its known inhibitory activities (11,12), CD300f can also exert cellular activation and is required for phagocytosis of apoptotic cells via recruitment of p85α of the PI3K signaling pathway (13,14). The finding that the genetic loci (human chromosome 17q22-25) of CD300 members are under strong positive evolutionary selection suggests potent immune regulatory roles for these molecules (15).…”

Inhibition of IL-32 and TSLP production through the attenuation of caspase-1 activation in an animal model of allergic rhinitis by Naju Jjok (Polygonum tinctorium)

“…They contribute to the pathology associated with allergic inflammatory conditions (29,30). Eosinophil accumulation in health and disease is a hallmark characteristic of mucosal immunity and type 2 helper T cell inflammation (31). The eosinophil granule proteins play a central role in the development of rhinitis (32).…”

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

“…Consequently, mouse CD300f has been shown to serve as either an activating or an inhibitory receptor (17,18,(45)(46)(47)(48). Our previous work showed that the CD300f cytoplasmic tail initiates either positive or negative signals for phagocytosis of ACs upon recognition of PS (17).…”