Neuroendocrine Peptides

The peripheral nervous system is connected with primary and secondary lymphoid organs through sensory nerves that may regulate immune responses through release of the neuropeptide calcitonin gene-related peptide (CGRP). Local and systemic levels of CGRP rapidly increase during inflammation caused by pathogens or tissue damage. The CGRP receptor in immune cells is coupled to heterotrimeric Gα_S proteins and initiates an increase in cellular cAMP levels leading to the activation of protein kinase A (PKA). CGRP modulates both innate and adaptive immune responses. Exposure of macrophages to CGRP during TLR4-driven stimulation impairs production of inflammatory cytokines such as TNF and IL-12, enhances production of the immunosuppressive cytokine IL-10, and promotes the generation of a regulatory macrophage phenotype. During adaptive immune responses, CGRP inhibits Th1 cell activity, but enhances effector functions of Th9 and Th17 cells. Consequently, CGRP plays an important role for the development and outcome of inflammatory disorders including sepsis, autoimmunity, and allergies.