MERTK in the trigeminal system: a novel target for cluster headache and other headache disorders?

Abstract The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER proto-oncogene tyrosine kinase (MERTK), a cell surface receptor, was strongly associated with cluster headache through genetic studies. Further, the MERTK ligand Galectin-3 has been found to be elevated in serum in migraine patients. In this study, MERTK and MERTK ligands were investigated in key tissue to better understand their potential implication in the pathophysiology of primary headache disorders. Immunohistochemistry was used to map MERTK and Galectin-3 expression in rodent trigeminal ganglia (TG). RT-qPCR was used to assess MERTK gene expression in blood and ELISA immunoassays were used for MERTK ligand quantification in serum from study participants with and without cluster headache. MERTK gene expression was elevated in blood samples from study participants with cluster headache patients as compared to controls. In addition, MERTK ligand Galectin-3 was found at increased concentration in the serum of study participants with cluster headache, while the ligands Growth Arrest Specific 6 and protein S levels were unaffected. MERTK and Galectin-3 were both expressed in rat TG. Galectin-3 was primarily located to smaller neurons and to a lesser extent in C-fibres, while MERTK was found in satellite glia cells (SGC) and in the outer membrane of Schwann cells. Interestingly, a strong MERTK signal was found specifically in the region proximal to the nodes of Ranvier. The overexpression of MERTK and Galectin-3 in study participants with cluster headache, as well as the presence of MERTK in peripheral SGC and Schwann cells in the TG, further highlights MERTK signalling as an interesting therapeutic target in primary headache.