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 7

HMGB1 amplifies renal inflammation by enhancing the NET/IL-33/ST2/NF-κB axis.

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HMGB1 amplifies renal inflammation by enhancing the NET/IL-33/ST2/NF-κB ...
(A) Schematic illustration of the SP-AKI mouse model induced by intratracheal instillation of Pseudomonas aeruginosa or saline in WT mice. (B) Experimental design of recombinant HMGB1 (rHMGB1) administration (50 μg/kg) in sham and SP-AKI model mice. (C) Experimental design of HMGB1 neutralization using anti-HMGB1 antibody (glycyrrhizin, 50 mg/kg) in sham and SP-AKI model mice. (D) Representative H&E-stained sections of lung and kidney tissues from mice of different experimental groups. 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. (E–G) Quantification of lung injury scores (E), renal tubular injury scores (F), and serum creatinine (Scr) levels (G) in WT control and SP-AKI model mice treated with rHMGB1 or anti-HMGB1 antibody. (H and I) Relative mRNA expression levels of HMGB1 (H) and IL-33 (I) in lung tissues from WT control and SP-AKI model mice following rHMGB1 administration or HMGB1 neutralization. (J and K) Serum MPO-DNA complex (J) and NE-DNA complex (K) levels in each group. (L and M) The percentage of neutrophils in whole blood cells (L) and BALF (M) of groups. (N) Representative flow cytometry plots showing CD11b+IL-33+ neutrophils in peripheral blood from the indicated groups. (O) Quantification of IL-33+ neutrophil percentages in groups from N. (P–U) Relative mRNA expression levels of IL-33 (P), ST2 (Q); inflammatory cytokines, including TNF-α (R) and IL-6 (S); and NF-κB pathway components, including RelA (T) and NF-κB1 (U), in kidney tissues from the indicated groups. Data are presented as mean ± SD. n = 5 per group. P values were calculated by 2-way ANOVA with post hoc Holm-Šídák test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. NS, no statistically significant difference.