Emerging roles of immune cell-derived neurotransmitters in immunity and disease

Immune cells have long been recognized for their important roles in tissue homeostasis and host defense. Increasing evidence reveals that many leukocytes synthesize and release classic neurotransmitters, including acetylcholine, norepinephrine, dopamine and γ-aminobutyric acid, under homeostatic and disease conditions. These immune cell-derived neuroactive molecules play significant roles in regulating immune cell activation, differentiation and effector functions through autocrine and paracrine modes. The neurotransmitter-producing immune cells have recently emerged as a pivotal bridge in neuroimmune crosstalk. In this review, we introduce this immune-intrinsic neurotransmitter system by presenting an up-to-date overview of production, signaling and functional consequences of neurotransmitters derived from immune cell across innate and adaptive compartments. Moreover, we outline the molecular mechanisms underlying neurotransmitter-mediated regulation of immune responses. Furthermore, we highlight the integrative neuroimmune signaling and explore their contribution to tissue homeostasis and disease pathogenesis in autoimmune disorders, cancer progression and infectious diseases. Based on preclinical and clinical evidence, we discuss the translational potential of targeting immune cell-intrinsic neurotransmitter pathways for treating human diseases.