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.
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.
Authors: Tiffany J Glass; Troy C Lund; Xiaobai Patrinostro; Jakub Tolar; Teresa V Bowman; Leonard I Zon; Bruce R Blazar Journal: Blood Date: 2011-05-26 Impact factor: 22.113