Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Mucosal Immunol. 2014 Mar;7(2):292-303. doi: 10.1038/mi.2013.47. Epub 2013 Jul 3.
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.
嗜酸性粒细胞在健康和疾病中的积累是黏膜免疫和 2 型辅助 T 细胞（Th2）炎症的标志特征。趋化因子（C-C 基序）受体 3（CCR3）诱导的趋化因子信号在嗜酸性粒细胞趋化反应中具有关键作用。然而，免疫受体酪氨酸基抑制基序（ITIM）受体如 CMRF35 样分子-1（CLM-1）的表达及其对嗜酸性粒细胞迁移的调控能力在很大程度上是未知的。我们现在报告说，CLM-1（但不是 CLM-8）在结肠和脂肪组织嗜酸性粒细胞中高度且明显表达。此外，Clm1⁻/⁻ 小鼠表现出基础组织嗜酸性粒细胞增多。CLM-1 负调控嗜酸性粒细胞对 eotaxin 的反应，包括嗜酸性粒细胞趋化、肌动蛋白聚合、钙内流和细胞外信号调节激酶（ERK）-1/2，但不磷酸化 p38。添加 CLM-1 配体（例如，磷脂酰丝氨酸）使野生型嗜酸性粒细胞在体外趋化性降低，而阻断 CLM-1/配体相互作用使野生型嗜酸性粒细胞在变应性气道疾病模型中的体外和体内趋化性增加。有趣的是，通过 CLM-1 抑制细胞募集是特异性的嗜酸性粒细胞和 eotaxin，因为白三烯 B₄（LTB₄）和巨噬细胞炎症蛋白-1α（MIP-1α）诱导的嗜酸性粒细胞和中性粒细胞迁移不受 CLM-1 的负调控。最后，从变应性鼻炎患者获得的外周血嗜酸性粒细胞显示出升高的 CLM-1/CD300f 水平。这些数据突出了 CLM-1 作为嗜酸性粒细胞稳态的新型调节剂，并表明嗜酸性粒细胞的积累不断受到 CLM-1 的调控，CLM-1 负调控 eotaxin 诱导的嗜酸性粒细胞反应。
