Interleukin-17D Produced by Alveolar Epithelial Type Ⅱ Cells Alleviates LPS-induced Acute Lung Injury Via the Nrf2 Pathway.

BACKGROUND Sepsis engenders an imbalance in the body's inflammatory response, with cytokines assuming a pivotal role in its progression. A relatively recent addition to the interleukin-17 family, denominated Interleukin-17D (IL-17D), is notably abundant within pulmonary confines. Nevertheless, its implication in sepsis remains somewhat enigmatic. This study endeavors to scrutinize the participation of IL-17D in sepsis-induced acute lung injury (ALI). METHODS The levels of IL-17D in the serum and bronchoalveolar lavage fluid(BALF) of both healthy cohorts and septic patients were ascertained through an ELISA protocol. For the creation of a sepsis-induced ALI model, intraperitoneal lipopolysaccharide(LPS) injections were administered to male C57/BL6 mice. Subsequently, we examined the fluctuations and repercussions associated with IL-17D in sepsis-induced ALI, probing its interrelation with nuclear factor erythroid 2-related factor 2(Nrf2), alveolar epithelial permeability, and heme oxygenase-1. RESULTS  IL-17D levels exhibited significant reduction both in the serum and BALF of septic patients. Similar observations manifested in mice subjected to LPS-induced acute lung injury (ALI). Intraperitoneal administration of recombinant Interleukin 17D protein(rIL-17D) prompted increased expression of claudin18 and concomitant enhancement of alveolar epithelial permeability, thus, culminating in improved lung injury. Alveolar epithelial type Ⅱ(ATⅡ) cells were identified as the source of IL-17D, regulated by Nrf2. Furthermore, a deficiency in HO-1 yielded elevated IL-17D levels, albeit administration of rIL-17D ameliorated the exacerbated pulmonary damage resulting from HO-1 deficiency. CONCLUSION  Nrf2 fosters IL-17D production within ATⅡ cells, thereby conferring a protective role in sepsis-induced ALI.