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 6

IL-33 and ST2 deficiency suppresses NET formation and NF-κB pathway activation in SP-AKI mice.

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IL-33 and ST2 deficiency suppresses NET formation and NF-κB pathway acti...
(A) Representative H&E, periodic acid–Schiff (PAS), and immunohistochemical staining of ST2 and NF-κB in kidney sections from control, IL-33–knockout (IL-33 KO), and ST2-knockout (ST2 KO) mice under sham and SP-AKI model conditions. Scale bars: 50 μm. Enlarged panels show 4-fold magnification of boxed regions. (B and C) Serum creatinine (Scr) levels and renal tubular injury scores in each group. (D and E) Quantification of ST2+ (D) and NF-κB+ (E) areas in kidney sections. (F–J) Relative mRNA expression levels of IL-6 (F), IL-1β (G), TNF-α (H), RelA (I), and NF-κB1 (J) in kidney tissues of groups. (K) Western blot showing the expression of MPO and CitH3 in kidney tissues from control and IL-33 KO mice under sham and SP-AKI conditions, with GAPDH as a loading control. (L and M) Semiquantitative analysis of MPO (L) and CitH3 (M) protein levels. (N) Western blot showing the expression of RelA in kidney tissues from control and ST2 KO mice under sham and SP-AKI conditions, with GAPDH as a loading control. (O) Semiquantitative analysis of RelA protein levels. (P) Schematic illustration of adoptive transfer of neutrophils isolated from the lungs of IL-33+/+ or IL-33–/– model mice into ST2–/– recipient mice under SP-AKI conditions. (Q) Representative H&E-stained lung and kidney sections from ST2 KO mice receiving neutrophils from WT or IL-33–/– mice. Scale bars: 100 μm (lung) and 50 μm (kidney). The enlarged panels represent 3-fold magnification in the lung images and 2-fold magnification in the kidney images. (R–T) Quantification of lung injury scores (R), renal tubular injury scores (S), and serum creatinine levels (T) in ST2 KO recipient mice following adoptive transfer. 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–J, L, M, and O) or 2-tailed Student’s t test (R and T). ***P < 0.001; ****P < 0.0001. NS, no statistically significant difference.