HMGB1-mediated formation of IL-33–abundant NETs drives lung-to-kidney injury in severe pneumonia–associated acute kidney injury
Mengqing Ma, Hao Zhang, Weijuan Deng, Xia Du, Mengxing Chen, Dawei Chen, Binbin Pan, Zhaowei Wang, Ting Chen, Caimei Chen, Xin Wan, Changchun Cao
Mengqing Ma, Hao Zhang, Weijuan Deng, Xia Du, Mengxing Chen, Dawei Chen, Binbin Pan, Zhaowei Wang, Ting Chen, Caimei Chen, Xin Wan, Changchun Cao
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Research Article Inflammation Nephrology Pulmonology

HMGB1-mediated formation of IL-33–abundant NETs drives lung-to-kidney injury in severe pneumonia–associated acute kidney injury

Abstract

Acute kidney injury (AKI) is a common and fatal complication of severe pneumonia, yet the mechanisms linking pulmonary inflammation to remote kidney injury remain poorly understood. Multicenter cohort data (n = 300) revealed that the incidence of severe pneumonia–associated AKI (SP-AKI) was 53.6%, with a mortality rate of 24.2%. SP-AKI was associated with elevated circulating levels of HMGB1, NETs, and IL-33. Murine experiments demonstrated that alveolar HMGB1 triggers the formation of IL-33–enriched NETs, which migrate to the kidney and activate tubular ST2/NF-κB signaling, driving inflammation and apoptosis. Genetic knockout of IL-33, ST2, or the NET-forming key enzyme PAD4, as well as pharmacological inhibition of HMGB1, IL-33, or NETs, all attenuated lung and kidney injury. Exogenous HMGB1 amplified NET-mediated IL-33 release, establishing a self-sustaining HMGB1/NET/IL-33 feed-forward loop. PAD4 deficiency completely blocked NET generation and disrupted HMGB1/IL-33 signaling. This study identified and validated a damage-associated molecular pattern–driven (DAMP-driven) HMGB1/NET/IL-33 signaling axis that mediates remote kidney injury in SP-AKI, redefining NETs from local effectors to cross-organ pathogenic carriers, thereby providing potential DAMP-targeted therapeutic avenues for SP-AKI.

Authors

Mengqing Ma, Hao Zhang, Weijuan Deng, Xia Du, Mengxing Chen, Dawei Chen, Binbin Pan, Zhaowei Wang, Ting Chen, Caimei Chen, Xin Wan, Changchun Cao

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Figure 4

IL-33 from neutrophils is required for NET-driven lung and kidney injury in SP-AKI.

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IL-33 from neutrophils is required for NET-driven lung and kidney injury...
(A and B) Representative flow cytometry plots and quantification of Ly6G+CD11b+ neutrophils in blood, kidney, and lung tissues following anti-Ly6G or IgG treatment. (C) Kaplan-Meier survival analysis of WT control mice, SP-AKI model mice, SP-AKI model mice treated with IgG, and SP-AKI model mice treated with anti-Ly6G antibody (250 μg/mouse) administered before (Pre-M) or after (Post-M) model induction. P value was determined by log-rank test. (D) Serum creatinine (Scr) levels in WT control and SP-AKI model mice treated with IgG, anti-Ly6G antibody Pre-M, or anti-Ly6G antibody Post-M. (E and F) Relative mRNA expression levels of IL-33 in lung (E) and kidney (F) tissues from each group. (G) Neutrophil adoptive transfer process in mouse lung tissues. IL-33+/+ mice representing the SP-AKI mouse model. All recipient mice for adoptive transfer underwent neutrophil depletion. (H) Scr levels were higher in IL-33+/+ model mice. (I and J) Relative IL-33 mRNA expression in lung (I) and kidney (J) tissues between IL-33+/+ and IL-33–/– model. (K) Representative H&E-stained sections of lung and kidney tissues from WT and IL-33–/– mice, as well as recipient mice following adoptive transfer of IL-33+/+ or IL-33–/– model neutrophils. Scale bars: 100 μm (lung) and 50 μm (kidney). The enlarged panels show 3-fold magnification of the boxed regions in the lung images and 2-fold magnification in the kidney images. (L and M) Histological injury scores of lung (L) and kidney (M) tissues in the indicated groups. (N) Serum creatinine levels in WT and IL-33–/– mice, as well as recipient mice following adoptive transfer of IL-33+/+ or IL-33–/– model neutrophils. Data are presented as mean ± SD. n = 5 per group. P values were calculated by 2-way ANOVA with post hoc Holm-Šídák test (B and D–F), 2-tailed Student’s t test (H–J), or 1-way ANOVA (L–N). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. NS, no statistically significant difference.