Work

Interleukin-36β inhibits CD4+CD25+ regulatory T cells by activating endoplasmic reticulum-phagy in septic mice

Year: 2025

Type: article

Abstract: CD4 + CD25 + regulatory T cells (Tregs) contribute to the pathogenesis of sepsis-induced immunosuppression. We have identified interleukin (IL)-36β as a critical cytokine regulating CD4 + CD25 + Treg activity. This study aimed to further investigate the underlying mechanism of IL-36β-triggered responses in murine CD4 + CD25 + Tregs in presence of lipolysaccharide (LPS) and in a mouse model of sepsis induced by cecal and puncture (CLP). Following LPS exposure, ER-phagy activity increased, peaked at 12 h, and then markedly declined. Furthermore, we observed that IL-36β could activate ER-phagy of CD4 + CD25 + Tregs under LPS challenge. Mechanistic investigations revealed the critical involvement of the endoplasmic reticulum (ER) stress-related protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-activating transcription factor 4 (ATF4) signaling axis in IL-36β-induced ER-phagy. Moreover, IL-36β knockout (IL-36β −/− ) strongly dampened ER-phagy and PERK-ATF4 signaling under LPS stimulation compared to the wild-type group. IL-36β-elicited effects on CD4 + CD25 + Tregs were significantly abrogated by FAM134B (the ER-phagy-specific receptor) knockout or salubrinal (a specific inhibitor of the PERK-ATF4 pathway). In addition, IL-36β was potent in diminishing serum levels of creatinine (Cr), aspartate transaminase (AST), and alanine transaminase (ALT) and attenuated histopathologic alterations in the liver, kidneys, and lungs of CLP mice. Importantly, the absence of IL-36β notably aggravated the survival rate of septic mice, indicating a beneficial role in septic prognosis. IL-36β can down-regulate the immune activity of CD4 + CD25 + Tregs via ER-phagy induction. Our study might provide novel targets for therapeutic strategies to prevent the development of sepsis. Schematic presentation of the potential role and regulatory mechanism underlying IL-36β in CD4 + CD25 + Tregs in sepsis. In the development of sepsis, IL-36β downregulates the immunosuppressive activity of CD4 + CD25 + Tregs via PERK-ATF4 pathway-mediated ER-phagy. IL-36β is potent in diminishing the expression of Foxp3 and CTLA-4 and reducing the production of IL-10 and TGF-β1 in CD4 + CD25 + Tregs, thereby activating effector T-cell function, as reflected by elevated levels of IL-2, a decreased ratio of IL-4 to IFN-γ, and increased proliferation of effector T cells. IL-36β-induced ER-phagy in CD4 + CD25 + Tregs might exert a beneficial impact on the prognosis of septic complications. • IL-36β-induced ER-phagy of CD4 + CD25+ Tregs. • The PERK-ATF4 pathway was critically involved in the impact of IL-36β on ER-phagy. • IL-36β exerted an inhibitory effect on CD4 + CD25+ Tregs by activating ER-phagy in sepsis. • IL-36β administration improved organ injury and survival rate in CLP-induced septic mice.

Source: International Immunopharmacology

DOI: 10.1016/j.intimp.2025.114349

Authors: Yun Ge, Xi Chen

Institutions: Zhejiang Provincial People's Hospital, Second Affiliated Hospital of Zhejiang University, Hangzhou Medical College, Zhejiang University

Language: English

Topic: T-cell and B-cell Immunology

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,220