Lack of S1PR2 in Macrophage Ameliorates Sepsis-associated Lung Injury through Inducing IL-33-mediated Type 2 Immunity.

The function of type 2 immunity and mechanisms underlying the initiation of type 2 immunity following sepsis-induced lung injury remain unclear. S1PR2 has been demonstrated to modulate type 2 immunity in the context of asthma and pulmonary fibrosis. Thus, this study aims to investigate the role of type 2 immunity and whether and how S1PR2 regulates type 2 immunity in sepsis. Peripheral type 2 immune response in septic patients and healthy controls were assessed. The impact of S1PR2 on type 2 immunity in septic patients and in a murine model of sepsis was further investigated. The type 2 innate immune responses were significantly increased in the circulation of patients 24 hours after sepsis, which was positively related to clinical complications and negatively correlated with S1PR2 mRNA expression. Animal studies showed that genetic deletion or pharmacological inhibition of S1PR2 induced type 2 innate immunity accumulation in the post-septic lungs. Mechanistically, S1PR2 deficiency promoted macrophage-derived interleukin (IL)-33 increase and associated type 2 response in the lung. Furthermore, S1PR2-regulated IL-33 from macrophage mitigated lung injury following sepsis in mice. In conclusion, a lack of S1PR2 modulates type 2 immune response by upregulating IL-33 release from macrophages and alleviates sepsis-induced lung injury. Targeting S1PR2 may have a potential therapeutic value for sepsis treatment.