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 5

Activation of the IL-33/ST2/NF-κB signaling pathway in the kidneys during SP-AKI.

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Activation of the IL-33/ST2/NF-κB signaling pathway in the kidneys durin...
(A) Western blot showing the expression of IL-33 and ST2 protein in kidney tissues from sham and SP-AKI model groups, with GAPDH as a loading control. (B and C) Semiquantitative analysis of IL-33 (B) and ST2 (C) protein levels. (D and E) Relative mRNA expression levels of IL-33 (D) and ST2 (E) in kidney tissues from sham and SP-AKI model mice. (F) Gene set enrichment analysis of a public scRNA-seq dataset (GSE210622) showing enrichment of the NF-κB and TNF signaling pathways in tubular epithelial cells (TECs). (G) Representative immunohistochemical staining of ST2 and NF-κB in kidney sections from sham and SP-AKI model mice. Scale bars: 50 μm. Enlarged panels show 3-fold magnification of boxed regions. (H and I) Quantification of ST2+ (H) and NF-κB+ (I) areas in kidney sections. (J) Western blot showing RelA (NF-κB subunit) expression in kidney tissues from sham and SP-AKI mice. (K) Semiquantitative analysis of RelA protein levels. (L and M) Relative mRNA expression levels of RelA (L) and NF-κB1 (M) in kidney tissues. Data are presented as mean ± SD. n = 5 per group. P values were calculated by 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.