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 3

Accumulation of IL-33–enriched NETs in SP-AKI kidneys.

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Accumulation of IL-33–enriched NETs in SP-AKI kidneys. (A) Representativ...
(A) Representative confocal images of immunofluorescent staining of Ly6G (green), MPO (pink), IL-33 (red), and DAPI (blue) in the lung, kidney, heart, spleen, and liver from mice with severe pneumonia. Scale bars: 50 μm. The enlarged panels represent 3-fold magnification of the boxed regions. (B) Uniform manifold approximation and projection (UMAP) visualization of public scRNA-seq data showing major kidney cell populations in non-AKI and SP-AKI patients (GSE210622). (C) Relative proportions of major cell types in non-AKI and SP-AKI patient kidneys. (D) Violin plots showing differentially expressed genes (DEGs) across major kidney cell populations between SP-AKI and non-AKI conditions, presented as log2(fold change). (E) Cell-cell communication analysis showing outgoing signaling patterns of secreting cells (left) and incoming signaling patterns of target cells (right) in SP-AKI patient kidneys. (F) Gene set enrichment analysis of the leukocyte transendothelial migration pathway in distal convoluted tubule (DCT), thick ascending limb (TAL), connecting tubule (CNT), and collecting duct (CD). (G) Western blot showing the expression of MPO and CitH3 in SP-AKI mouse kidney. (H and I) Semiquantitative analysis of MPO (H) and CitH3 (I) protein levels. (J) Representative immunofluorescence images showing PAD4, IL-33, and Ly6G expression in SP-AKI mouse kidney sections from sham and model mice, with merged and enlarged views. Scale bars: 50 μm. Enlarged panels show 3-fold magnification of boxed regions. Data are presented as mean ± SD. n = 5 per group. P values were calculated by 2-tailed Student’s t test. ****P < 0.0001.