Cmrf-35-Like Molecule 1 (CLM-1) Is Required For IL-4-Induced Cellular Responses and Development Of Allergic Airway Inflammation

Mr. Itay Moshkovits, Mrs. Danielle Karo-Atar, Mrs. Dana Shik, Dr. Alon Hershko, MD, PhD, Dr. Ariel Munitz, PhD

Abstract: 

Rationale

IL-4 is critically involved in the development of Th2-immune responses. Surprisingly, endogenous molecular mechanisms regulating IL-4-induced responses are largely unknown. CMRF-35-like molecule-1 (CLM-1) is an immunoreceptor tyrosine-based inhibitory motif-containing receptor. Yet, its role Th2 immune responses is unclear.

 

Methods

Wild type (WT), and Clm1-/- mice were intranasally challenged with Aspergillus fumigatus extract or IL-4. Lung cellular expression of CLM-1 (Flow), cytokine/chemokine and IgE levels were assessed (ELISA). IL-4/IL-13-induced mediator secretion and STAT-6 phosphorylation were assessed in bone marrow (BM)-derived macrophages (Mφ) and eosinophils (BM-Eos). CLM-1 expression was assessed in human peripheral blood monocytes and eosinophils from healthy and allergic patients.

 

Results

CLM-1 was specificllay upregulated by lung eosinophils and macrophages following aeroallergen-challenge, a phenomenon, which was recapitulated in-vitro and in-vivo by IL-4. IL-4/IL-13-stimulated Clm1-/- BM-Mφ and BM-Eos displayed decreased cytokine/chemokine secretion and STAT-6 phosphorylation compared with WT cells. Furthermore, IL-4-induced “priming” of eosinophil chemotaxis was absent in Clm1-/- BM-Eos. Consistently, activation of CLM-1 by antibody cross-linking enhanced IL-4 induced responses in BM-Mφ. In-vivo, IL-4-challenged Clm1-/- mice displayed decreased cellular infiltration and reduced cytokine/chemokine secretion compared with WT mice. Similiarly, aeroallergen-challenged Clm1-/- mice were protected from allergic airway inflammation and exhibited reduced IgE levels, decreased lung cellular infiltration and decreased chemokine levels. Finally, CLM-1 expression was increased in monocytes and eosinophils obtained from allergic patients compared to healthy individuals.

 

Conclusions

Our data demonstrates that CLM-1 is required for the development of allergic airway disease by co-activating IL-4-induced responses. These data highlight CLM-1 as a potential novel therapeutical target for asthma treatment.

abstract No: 

590
    • AAAAI 2014 (70th)