The sterols–LXR axis alleviates IL-17-mediated acute inflammatory response in Apostichopus japonicus

Abstract

Inflammation plays a crucial role in defending the host against pathogens and other harmful stimuli. However, uncontrolled acute inflammation has been implicated in a multitude of diseases, including those that affect aquatic animals. While the processes that initiate the inflammatory response are relatively well understood, the roles of lipids, their derivatives, and the mechanisms by which they contribute to alleviating acute inflammation remain less well characterized. In the present study, lipidomic analyses were performed to identify changes in lipid metabolism in the coelomocytes of the sea cucumber Apostichopus japonicus after infection with Vibrio splendidus. The omics data indicated significant increases in specific sterols, including desmosterol, 25-hydroxycholesterol, and 24,25-epoxycholesterol, during the late phase of the inflammatory response. The accumulation of these sterols was found to be responsible for the suppression of A. japonicus interleukin-17 (AjIL-17)-mediated inflammatory response. A subsequent biolayer interferometry assay revealed that A. japonicus liver X receptor (AjLXR) served as the downstream receptor of these sterols. The knockdown of AjLXR reversed the desmosterol-dependent suppression of AjIL-17 expression. Conversely, the activation of AjLXR by the synthetic agonist GW3965 inhibited the expression of AjIL-17 induced by infection with V. splendidus or stimulation with LPS. Moreover, AjLXR repressed AjIL-17 transcription by directly binding to the AjIL-17 promoter in a SUMOylation-independent manner. In conclusion, our findings highlight the crucial role of the sterols–LXR axis in mitigating IL-17-mediated acute inflammation, suggesting that targeting this axis could be a promising strategy for preventing and treating chronic inflammation-associated diseases.

Keywords

Sterols / LXR / IL-17 / Acute inflammation / Alleviation

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