Adhesion GPCRs in inflammatory diseases of the human brain
Jörg Hamann, University of Amsterdam
Microglia are instrumental for brain development and homeostasis, and alterations in their functioning contribute to the onset and progression of diseases of the central nervous system (CNS). Using RNA sequencing, we identified GPR56, an adhesion G proteincoupled receptor (aGPCR) involved in neuronal development, as a ‘top-3’ seven-span transmembrane receptor in human grey and white matter microglia. The only other immune cells that express GPR56 are cytotoxic lymphocytes, where GPR56 restricts different effector functions. Microglia in normal-appearing grey and white matter from multiple sclerosis donors showed a tendency towards lower GPR56 transcript levels. In contrast, transcripts levels of GPR133, a widely distributed aGPCR associated with fitness-related functions that has not been studied in immune cells so far, were increased. We postulate that changes in aGPCR expression and signaling control the cellular state of microglia and contribute to the pathophysiology of human brain disorders. Exploring these changes will increase our understanding of the perturbations that microglia activation generates in the CNS environment and may open possibilities for the development of novel therapeutic approaches. We aim to study the role of aGPCRs expression and signaling in microglia functioning and neuroinflammation. Our research will benefit from the unique access to fresh human brain tissue, provided by the Netherlands Brain Bank. We will combine studies of purified human microglia in vitro with investigations of genetically modified microglia in zebrafish in vivo. The project has three objectives: (1) Assessing the regulation of aGPCR expression in microglia isolated from different human brain regions and diseases; (2) Identifying the role of GPR56 (and possibly other aGPCRs) in immune functions of freshly isolated human microglia; and (3) Testing the involvement of GPR56 (and other aGPCRs) in microglia development, distribution, and function in zebrafish.