Lysyl oxidase-dependent bone marrow stiffening promotes neutrophil activation in diabetes

Persistent neutrophil activation contributes to the development of diabetic vascular complications in many organs including the retina. Past studies have implicated abnormal molecular or biochemical cues in neutrophil activation. Here we show that neutrophils can also be mechanically activated through an increase in bone marrow (BM) stiffness that results from diabetes-induced overexpression of matrix collagens and their crosslinker lysyl oxidase (LOX). Administration of LOX inhibitor β-aminopropionitrile (BAPN) in diabetic mice concomitantly blocked BM matrix stiffening and neutrophil activation (superoxide generation and gp91^phox upregulation), which predictably inhibited neutrophil cytotoxicity towards co-cultured retinal endothelial cells. Further, culturing neutrophils within BM-mimicking hydrogels of tunable stiffness indicate that matrix-localized and soluble LOX act synergistically to mechanochemically activate neutrophils in the BM. Thus, LOX-dependent changes in the BM physical environment offer a new mechanistic basis and therapeutic target for diabetic complications marked by neutrophil activation.