Acetylcholine promotes autoreactive B cell response

Researchers have identified a novel function of acetylcholine produced by spleen fibroblastic reticular cells (FRCs) in driving autoimmune responses systemic lupus erythematosus (SLE), according to new study published Cell Metabolism recently.1 The links the neurotransmitter lipid metabolism autoreactive B pathogenesis SLE. Energy demands are dramatically increased activated cope with their proliferation and effector functions. Accumulating evidence suggest that germinal center (GC) tend uptake utilize fatty acids for mitochondrial respiration. Metabolic changes including metabolisms been involved diseases, “The specific roles cell SLE not determined yet,” remarks Hui Zhang, one responding authors study. first showed from patients (and lupus-prone mice) preferentially rely on acid oxidation (FAO) as source energy. Importantly, inhibition FAO suppressed GC differentiation, reduced autoantibody production, ameliorated pathology mice. Although carrying receptors (BCRs) low affinity autoantigens prevalent healthy individuals, absence high-affinity BCRs self-antigens prevents development “High-affinity usually generated through somatic hypermutation. receive signals neighboring lymphocytes, dendritic cells, stromal FRCs, during response. microenvironment need be identified.” Zhang. is complex organ multiple functions homeostasis immune responses. In spleen, antigen-experienced differentiate follicles white pulp. FRCs heterogeneous form dense network spleen. “Regarding critical follicle formation, we hypothesized could play role SLE,” explains Niansheng Yang, corresponding authors. By using an elegant vitro coculture system, researchers demonstrated enhanced upregulation CD36/FABP4. Further, transferred into mice, finding out FRC injection upregulated further analyzing they found number reacting double-stranded DNA was expanded injection, which led autoimmunity deposition kidney. “Anatomically, most locate at T zone pulp, outside GC,” says “If directly regulation GC, should act producing cues cells.” To uncover how regulate underlying mechanisms, screened culture supernatant promoted production acetylcholine. Acetylcholine reprogrammed vivo, transfer normal numbers. contrast, acetylcholine-deficient no effects Systemic kidney were also affected FRCs. Regarding acetylcholine-mediated intracellular signaling, stimulation release calcium endoplasmic reticulum influx ORAI channel, cells. “This provides mechanistic insights understand contribute significantly response Targeting cholinergic signaling mechanism normalize serve therapeutic targets humans Yang.