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Serotonin suppresses lung ILC2 activation and proliferation

Cellular & Molecular Immunology volume 20, pages 546–547 (2023)Cite this article

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In recent issue, Wang et al. [1] reported the suppressive effects of serotonin (5-hydroxytryptamine, 5-HT) on the activation and proliferation of group 2 innate lymphoid cells (ILC2s) in the lungs. ILC2s belong to a family of newly appreciated immune cells with a broad impact on a variety of immunological functions [2]. In particular, ILC2 activation has been implicated in the pathophysiology of asthma [3]. Although serotonin is known to play important roles in diverse physiological functions in the body [4], the effects of serotonin on innate lymphoid cells are less understood. The findings described here could potentially establish a new therapeutic avenue for respiratory disorders.

The serotonin theory of depression states that lower levels of serotonin are associated with depression [5]. This influential theory is supported by the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) [6], even though a recent comprehensive review of the experimental data was unable to substantiate this theory [7]. Nonetheless, the current study used a cohort of patients with different severities of depression and found augmented production of IL-5 and IL-13 by their peripheral blood mononuclear cells upon in vitro stimulation relative to that of corresponding cells from healthy controls. The levels of serotonin appeared to be inversely correlated with those of IL-5 or IL-13. The severity of depression according to the total scores of the Hamilton Rating Scale for Depression (HAMD-17) also correlated inversely with the frequency of blood ILC2s. Furthermore, treatment of the patients with SSRI antidepressants led to a reduction in the ILC2 frequency in patients who achieved remission compared to those who did not. In mice, SSRIs also caused decreases in the number of lung ILC2s and their proliferation, as indicated by Ki67 expression during a papain-induced type 2 immune response. These effects were accompanied by the suppression of eosinophil recruitment to the lungs and IL-5 and/or IL-13 production by ILC2s. Likewise, intratracheal delivery of serotonin (5-HT) along with papain significantly diminished the peribronchial infiltration of leukocytes, especially those identified by periodic acid-Schiff (PAS) staining. Papain-induced eosinophil recruitment as well as ILC2 activation and proliferation were also restrained by 5-HT. Together, the data suggest the therapeutic potential of serotonin or SSRIs for dampening the activities of ILC2s in the lungs. However, the pharmacokinetics and route of delivery must be carefully determined. Although a more comprehensive study would be beneficial, the revelation of an inverse correlation between serotonin levels and ILC2 activities is interesting. Whether patients with severe depression exhibit any abnormalities associated with augmented ILC2 function in the respiratory system remains to be investigated. Paradoxically, serotonin has been reported to correlate positively with asthma in humans and mice, which illustrates the complexity of serotonin function [8, 9]

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  1. Oklahoma Medical Research Foundation, Program in Arthritis and Clinical Immunology, Oklahoma City, OK, USA

    Xiao-Hong Sun

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Sun, XH. Serotonin suppresses lung ILC2 activation and proliferation. Cell Mol Immunol 20, 546–547 (2023). https://doi.org/10.1038/s41423-023-00996-0

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