Pulmonary ILC2-derived serotonin mediates RSV-evoked airway hyperreactivity in mice

Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, lung epithelial cell-released IL-33 is elevated and promotes group 2 innate lymphoid cells (ILC2s) activation, leading to type 2 cytokines production and asthma development. Serotonin is a neurotransmitter involved in numerous biological functions in the central nervous system as well as peripheral tissues. Previous studies have found elevated serotonin levels in plasma and bronchoalveolar lavage fluid (BALF) from asthma patients, implying that serotonin may involve in the pathogenesis of asthma. Therefore, we aimed to elucidate the role of ILC2-released serotonin in the regulation of RSV-induced airway hyperreactivity (AHR). To investigate whether ILC2 would secrete serotonin upon activation, pulmonary ILC2s were sorted from C57BL/6 mice and then treated with IL-33 in vitro, and we found an increase in the production of serotonin from IL-33-activated ILC2s. Furthermore, elevated BALF serotonin levels were also found in RSV-infected mice. Moreover, we clarified that ILC2 as a major source of serotonin during RSV infection. Next, to determine the role of serotonin in RSV-evoked AHR, we found that the treatment of Clozapine (serotonin receptor inhibitor) significantly attenuated AHR and decreased IL-13 expression. Meanwhile, we demonstrated that the administration of exogenous serotonin exacerbated RSV-caused AHR. Furthermore, serotonin enhanced IL-5 and IL-13 production from IL-33-activated ILC2 in vitro. Taken together, our results indicated that pulmonary ILC2-derived serotonin contributes to RSV-evoked AHR and exacerbates type 2 cytokines through a positive regulation of ILC2 function.