Neuron-derived neuropeptide Y fine-tunes the splenic immune responses

The nervous and immune systems are closely entwined to maintain the immune balance in health and disease. Here, we showed that LPS can activate suprarenal and celiac ganglia (SrG-CG) neurons and upregulate NPY expression in rats. Single-cell sequencing analysis revealed that knockdown of the NPY gene in SrG-CG altered the proliferation and activation of splenic lymphocytes. In a neuron and splenocyte coculture system and in vivo experiments, neuronal NPY in SrG-CG attenuated the splenic immune response. Notably, we demonstrated that neuronal NPF in Drosophila exerted a conservative immunomodulatory effect. Moreover, numerous SNPs in NPY and its receptors were significantly associated with human autoimmune diseases, which was further supported by the autoimmune disease patients and mouse model experiments. Together, we demonstrated that NPY is an ancient language for nervous-immune system crosstalk and might be utilized to alleviate inflammatory storms during infection and to modulate immune balance in autoimmune diseases. •LPS activates SrG-CG neurons and dramatically upregulates NPY gene expression in rats•SrG-CG neuronal NPY suppresses the bacteria or LPS-elicited inflammatory response•NPY/F has a conserved function in fine-tuning immune balance in different species•NPY and its receptors are associated with human autoimmune diseases Yu, Xiao, et al. identify NPY/F as an ancient language for the crosstalk between the nervous system and the immune system in different species. Neuronal NPY is dramatically elevated during infection and plays an important role in fine-tuning immune balance in inflammatory response and autoimmune diseases.