H4 histamine receptor mediates optimal migration of mast cell precursors to CXCL 12

Background: CXCL12, a constitutive chemokine (ligand of CXCR4 and CXCR7), is expressed in the skin and airway epithelium and plays a significant role in allergic airway diseases. The pleiotropic effects of CXCL12 are enhanced by cofactors specific to the target cell. Objective: We hypothesized that histamine, a major mediator of allergic reactions, could interact with CXCL12 to promote human mast cell (MC) migration. Methods: The chemotactic effects of CXCL12 alone or in combination with histamine were evaluated on human precursor and mature MCs by using in vitro migration assays. Results: CXCL12 exerts a chemotactic activity on both precursor and fully mature MCs. Histamine and supernatants from IgE-activated MCs enhanced CXCL12 chemotactic activity on the precursor MC population. The synergy between histamine and CXCL12 was not observed with mature MCs, CD4(+) T cells, and monocytes. Inhibition of histamine receptors pharmacologically or with specific small interfering RNA (siRNA) indicated that synergy between histamine and CXCL12 required the H-4 receptor. Conclusion: Histamine released by allergen-activated mature MCs might promote MC-rich allergic inflammation by enhancing recruitment of their precursors in tissues constitutively expressing CXCL12, including skin and airways. Clinical implications: This work highlights a novel role of the H-4 receptor in the perpetuation of allergic responses and provides evidence for the Utility of H-4 receptor antagonists in the treatment of allergic diseases.