TIM-4 Regulates Allergic Airway Inflammation and Mast Cell Activation by Binding to CD300b.

Background: Although T cell immunoglobulin and mucin domain-4 (TIM-4) is involved in immune regulation, the function of TIM-4 in allergic responses is not understood. We investigated the effects of anti-TIM-4 monoclonal antibody (mAb) in a murine model of allergic airway inflammation. Methods: Anti-mouse TIM-4 mAb was administered to various allergic airway inflammatory model mice. A soluble form of TIM-4 (sTIM-4) was detected by newly developed a sandwich Enzyme-Linked Immunosorbent Assay (ELISA) and immunoblotting using anti-mouse or human TIM-4 mAbs. Bone marrow-derived mast cells (BMMCs) were generated from C57BL/6 and CD300b-deficient mice to determine the contribution of sTIM-4 to mast cell activation. The concentrations of serum sTIM-4 in patients with asthma in 124 adult patients were quantified using ELISA. Results: Accumulation of eosinophils and production of T helper type 2 (Th2) cytokines in the lung were significantly reduced in anti-TIM-4-treated mice. High amounts of sTIM-4 through proteolytic cleavage were detected in bronchoalveolar lavage fluid and sera from allergic airway inflammatory mice. sTIM-4 induced proinflammatory cytokine production in mast cells by interacting with CD300b. We also detected human sTIM-4 on TIM-4 transfected cells, which induced interleukin-6 (IL-6) production in a human mast cell line. Moreover, serum sTIM-4 levels were associated with asthma severity in patients with asthma. Conclusion: TIM-4 contributes significantly to the effector phase of allergic airway inflammation. TIM-4 may serve as a therapeutic target and sTIM-4 may have the potential to be used as surrogate marker in asthma.