Trevizan-Bau, P.; Ringuet, M. T.; Daglas, M.; Devi, S.; Monard, S. C.; Loi, K.; Luo, Z.; Weier, A.; Dryburgh, L.; Alexandre, Y. O.; Lee, H. J.; Li, S.; Rawlinson, D.; Canner, E. A.; Schienstock, D.; Horsnell, H. L.; Burn, T. N.; Fransos, Z.; Mohammed, S. F.; Kedzierski, L.; Foo, I. J. H.; Di Natale, M.; Moreira, M. D. L.; Molero, J. C.; Dodd, G. T.; Kedzierska, K.; Mackay, L. K.; Haque, A.; Sloan, E. K.; Schroeder, J.; McAllen, R. M.; Furness, J. B.; Mueller, S. N.

The central nervous system interprets inflammatory signals in the body and directs the modulation of inflammatory responses by reflexively engaging peripheral sympathetic neurons. This includes sympathetic neurons that innervate the spleen, which can regulate immune functions and modulate inflammation. Yet, it is unclear if neuroimmune interactions involve specialised immunoregulatory sympathetic neurons, and if the immune system can reciprocally regulate peripheral sympathetic neurons to control these responses. Using retrograde tracing and single-cell transcriptomics, we find that spleen-innervating neurons are heterogeneous but do not exhibit a distinct transcriptional program indicative of specialisation for immune communication. However, we report that immune responses induced by pathogens can regulate postganglionic sympathetic neuron functions. Cytokines produced by immune cells downregulate expression of the neurotrophin nerve growth factor in spleen mesenchymal cells, leading to organ-specific sympathetic nerve retraction from the spleen. Concurrently, splenic type I interferon signalling induces inflammatory gene expression in neurons and suppresses neuron excitability. Chemogenetic activation of sympathetic neurons demonstrates an impaired anti-inflammatory capacity in the spleen during infection. These results reveal regulation of sympathetic neuronal functions by the immune system, which could support optimal generation of immune responses against pathogens.