Succinic Acid-Induced Macrophage Endocytosis Promotes Extracellular Vesicle-Based Integrin Beta1 Transfer Accelerating Fibroblast Activation and Sepsis-Associated Pulmonary Fibrosis.

Abstract

Sepsis-associated pulmonary fibrosis (SAPF) is a life-threatening condition driven by persistent fibroblast activation and excessive extracellular matrix (ECM) deposition. While metabolic reprogramming, profibrotic extracellular vesicles (EVs), and integrin activation are implicated in pulmonary fibrosis, their interplay remains unclear. This study reveals that succinic acid, a product of glycometabolic reprogramming, promotes macrophage-mediated endocytosis, driving the release of profibrotic EVs. These EVs transfer integrin beta1 (ITGβ1) from macrophages to fibroblasts, activating fibroblasts and advancing SAPF. Through Single-cell RNA sequencing (scRNA-seq), proteomics, immunofluorescence, and electron microscopy, the critical role of EV-mediated ITGβ1 transfer in macrophage-fibroblast communication is identified. Knockdown of ITGβ1 or Alix, a mediator of multivesicular bodies (MVBs) biogenesis, inhibited profibrotic EVs formation and alleviated SAPF. These findings highlight a novel mechanism in that the transfer ITGβ1 via EVs plays a critical role in macrophage-fibroblast communication, representing a novel mechanism underlying SAPF. Targeting EV-mediated ITGβ1 transfer can provide a promising therapeutic strategy to alleviate the progression of SAPF.