TY - JOUR
T1 - CMRF35-like molecule 1 (CLM-1) regulates eosinophil homeostasis by suppressing cellular chemotaxis
AU - Moshkovits, I.
AU - Shik, D.
AU - Itan, M.
AU - Karo-Atar, D.
AU - Bernshtein, B.
AU - Hershko, A. Y.
AU - Van Lookeren Campagne, M.
AU - Munitz, A.
N1 - Funding Information:
This study was supported by research funding to AYH (Morasha Program, Israel Science Foundation, grant 1084/10); to IM by the Joan and Jaime Constantiner Institute for Molecular Genetics; to AM by the FP7 Marie-Curie Reintegration grant (grant 256311), the US-Israel Binational Science Foundation (grants 2009222 and 2011244), the Israel Science Foundation (grant 955/11), the Israel Cancer Research Foundation Research Career Development Award, the Dream Ideas Djerassi-Elias Institute of Oncology Research Fund, and internal Tel-Aviv University funds. We thank Drs Jamie and Nancy Lee (Mayo Clinic, Scottsdale, AZ) for the anti-MBP antibody and Dr Steffen Jung (Weizmann Institute, Rehovot, Israel) for providing critical reagents for this study. Itay Moshkovits performed this work in partial fulfillment of the requirements for a PhD degree at the Sackler Faculty of Medicine, Tel-Aviv University, Israel.
PY - 2014/3
Y1 - 2014/3
N2 - 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 B 4 (LTB 4)- and macrophage inflammatory protein-1 (MIP-1)-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.
AB - 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 B 4 (LTB 4)- and macrophage inflammatory protein-1 (MIP-1)-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.
UR - http://www.scopus.com/inward/record.url?scp=84890983592&partnerID=8YFLogxK
U2 - 10.1038/mi.2013.47
DO - 10.1038/mi.2013.47
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AN - SCOPUS:84890983592
SN - 1933-0219
VL - 7
SP - 292
EP - 303
JO - Mucosal Immunology
JF - Mucosal Immunology
IS - 2
ER -
