IGFBP6 orchestrates antiinfective immune collapse in murine sepsis via prohibitin-2–mediated immunosuppression
Kai Chen, Ying Hu, Xiaoyan Yu, Hong Tang, Yanting Ruan, Yue Li, Xun Gao, Qing Zhao, Hong Wang, Xuemei Zhang, David Paul Molloy, Yibing Yin, Dapeng Chen, Zhixin Song
Kai Chen, Ying Hu, Xiaoyan Yu, Hong Tang, Yanting Ruan, Yue Li, Xun Gao, Qing Zhao, Hong Wang, Xuemei Zhang, David Paul Molloy, Yibing Yin, Dapeng Chen, Zhixin Song
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Research Article Infectious disease Inflammation

IGFBP6 orchestrates antiinfective immune collapse in murine sepsis via prohibitin-2–mediated immunosuppression

Abstract

The persistent challenge of sepsis-related mortality underscores the necessity for deeper insights. Our multicenter, cross-age cohort study identified insulin-like growth factor binding protein 6 (IGFBP6) as a critical regulator in sepsis diagnosis, prognosis, and mortality risk evaluation. Mechanistically, IGFBP6 engages in IGF-independent binding to prohibitin2 (PHB2) on epithelial cells, driving PHB2 tyrosine phosphorylation during sepsis. This process disrupts STAT1 phosphorylation, nuclear translocation, and its recruitment to the CCL2 promoter, ultimately impairing CCL2 transcription and macrophage chemotaxis. Crucially, PHB2 silencing via siPHB2 and STAT1 activation using 2-NP restored CCL2 expression in vitro and in vivo, improving bacterial clearance and survival in septic mice. Concurrently, IGFBP6 compromised macrophage bactericidal activity by inhibiting Akt phosphorylation, reducing ROS/IL-1β production and phagocytic capacity — defects reversible by Akt agonist SC79. Collectively, IGFBP6 emerges as an endogenous driver of sepsis pathogenesis, positioning it as a dual diagnostic biomarker and therapeutic target. Intervention strategies targeting IGFBP6-mediated signaling may offer transformative approaches for sepsis management.

Authors

Kai Chen, Ying Hu, Xiaoyan Yu, Hong Tang, Yanting Ruan, Yue Li, Xun Gao, Qing Zhao, Hong Wang, Xuemei Zhang, David Paul Molloy, Yibing Yin, Dapeng Chen, Zhixin Song

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Figure 1

IGFBP6 as a diagnostic and prognostic biomarker in adult sepsis.

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IGFBP6 as a diagnostic and prognostic biomarker in adult sepsis. (A) Dis...
(A) Discovery cohort (sepsis: n = 91; non-septic infection controls: n = 42; healthy controls: n = 48). Validation cohort (sepsis: n = 163; non-septic infection controls: n = 116; healthy controls: n = 92). (B) Serum IGFBP6 levels in discovery cohort (ELISA). (C) Comparison of serum IGFBP6 levels in patients with sepsis (n = 65) and patients with septic shock (n = 26) in discovery cohort. (D) Serum IGFBP6 levels in survivors with sepsis (n = 75) versus non-survivors with sepsis (n = 16) in discovery cohort. (E and F) Dynamics of serum IGFBP6 levels in randomly selected survivors (E) and non-survivors (F) at days 1, 3, or 7. (G) ROC analysis for mortality prediction comparing IGFBP6, SOFA score, PCT/CRP concentrations, and WBC and platelet counts (discovery cohort). (H) Kaplan-Meier survival curves stratified by IGFBP6 cutoff value (221.1 ng/mL) at ICU admission (discovery cohort). (I) Serum IGFBP6 levels in validation cohort (ELISA). (J) IGFBP6 levels in patients with sepsis (n = 102) versus septic shock (n = 61) (validation cohort). (K) Serum IGFBP6 levels in survivors (n = 102) versus non-survivors (n = 61) in validation cohort. (L and M) Dynamics of IGFBP6 levels during 1, 3, and 7 days of ICU admission in validation cohort survivors (L) and non-survivors (M). (N) ROC curves comparing IGFBP6, SOFA, APACHE II, PCT, CRP, and WBC for mortality prediction (validation cohort). (O and P) Kaplan-Meier survival analysis using IGFBP6 cutoffs of 209.7 ng/mL (O) and 221.1 ng/mL (P) in validation cohort. Numbers and percentages indicate individuals; horizontal bars in B–F and I–M represent mean; Student’s t test in C, D, J, and K; 1-way ANOVA in B, E, F, I, L, M; log-rank test in H, O, and P. CRP, C-reactive protein; ICU, intensive care unit; PCT, procalcitonin; SOFA, sequential organ failure assessment.