Inhibition of PI3K p110δ rebalanced Th17/Treg and reduced macrophages pyroptosis in LPS-induced sepsis

Shiyun Zhang; Jiajia Shan; Yiyang Jie; Xian Zhang; Minyi Zhu; Jingwen Shen; Kefan Mao; Wenhao Chen; Yong Wang; Yanting Wen

doi:10.1016/j.molimm.2024.04.008

Inhibition of PI3K p110δ rebalanced Th17/Treg and reduced macrophages pyroptosis in LPS-induced sepsis

Mol Immunol. 2024 Apr 22:170:110-118. doi: 10.1016/j.molimm.2024.04.008. Online ahead of print.

Authors

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China.
² State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China. Electronic address: yongwang@nju.edu.cn.
³ State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China. Electronic address: wenyanting@nju.edu.cn.

PMID: 38653076
DOI: 10.1016/j.molimm.2024.04.008

Abstract

Sepsis is a systemic inflammatory response syndrome caused by trauma or infection, which can lead to multiple organ dysfunction. In severe cases, sepsis can also progress to septic shock and even death. Effective treatments for sepsis are still under development. This study aimed to determine if targeting the PI3K/Akt signaling with CAL-101, a PI3K p110δ inhibitor, could alleviate lipopolysaccharide (LPS)-induced sepsis and contribute to immune tolerance. Our findings indicated that CAL-101 treatment improved survival rates and alleviated the progression of LPS-induced sepsis. Compared to antibiotics, CAL-101 not only restored the Th17/regulatory T cells (Treg) balance but also enhanced Treg cell function. Additionally, CAL-101 promoted type 2 macrophage (M2) polarization, inhibited TNF-α secretion, and increased IL-10 secretion. Moreover, CAL-101 treatment reduced pyroptosis in peritoneal macrophages by inhibiting caspase-1/gasdermin D (GSDMD) activation. This study provides a mechanistic basis for future clinical exploration of targeted therapeutics and immunomodulatory strategies in the treatment of sepsis.

Keywords: CAL-101; Macrophages; PI3K/Akt signaling pathway; Pyroptosis; Sepsis; Treg.