The Chemokine System as a Therapeutic Target in Autoimmune Thyroid Diseases: A Focus on the Interferon-γ Inducible Chemokines and their Receptor

Mario      Rotondi; Luca      Chiovato

doi:10.2174/138161211798157559

Abstract

The recruitment, trafficking, and in situ maintenance of specific subsets of activated lymphocytes constitute crucial steps for the initiation and perpetuation of chronic autoimmune inflammation. The fact that, after IFN-γ stimulation, thyrocytes secrete CXCR3- binding chemokines, which in turn recruits Th1 lymphocytes expressing CXCR3 and secreting IFN-γ, strongly supports the concept that the interferon-γ inducible chemokines (CXCL9, CXCL10, and CXCL11) and their receptor CXCR3 play an important role in the initiation of autoimmune thyroid diseases (AITD). Thus, interfering with CXCR3 might result in the abrogation of the inflammatory process. The understanding of these pathogenetic mechanisms suggested novel therapeutic approaches, with a growing interest for finding a way to interrupt the interactions between chemokines and their receptors. In this review, we focus on the efforts performed in establishing new pharmacological compounds able to target the chemokine/chemokine receptors system as well as to prevent the secretion of CXCR3-binding chemokines, induced by pro-inflammatory cytokines. The crucial issue of selecting the relevant therapeutic targets in animal models of AITD was also discussed. Although some encouraging results have been reached, major hurdles were encountered on the way to success. As a result, we are still waiting for the first anti-chemokine anti-inflammatory drug. Given the importance of leukocytes recruitment to inflammatory sites, research will continue to address the issue of developing specific chemokinereceptor antagonists. We look forward to the development of these novel pharmacological compounds which will hopefully provide a more valid alternative to the currently used lifelong replacement therapies for AITD.

Keywords: Chemokines, autoimmunity, autoimmune thyroid disease, CXCL9, CXCL10, CXCL11, CXCR3, Graves' disease, Hashimoto's thyroiditis, psoriasis