Non-Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

A miRNA-CXCR4 signaling axis impairs monopoiesis and angiogenesis in diabetic critical limb ischemia.

Abstract

Patients with peripheral artery disease (PAD) and diabetes have the highest risk of critical limb ischemia (CLI) and amputation, yet the underlying mechanisms remain incompletely understood. MicroRNA (miRNA)-sequencing of plasma from diabetic patients with or without CLI was compared to diabetic mice with acute or subacute limb ischemia to identify conserved miRNAs. miRNA knockout mice on high fat diet were generated to explore impact on CLI. Comparison of dysregulated miRNAs from diabetic human subjects with PAD and diabetic mice with limb ischemia revealed conserved miR-181 family members. High fat-fed, diabetic Mir181a2b2 knockout (KO) mice had impaired revascularization in limbs due to abrogation of circulating Ly6Chi monocytes with reduced accumulation in ischemic skeletal muscles. M2-like KO macrophages under diabetic conditions failed to produce pro-angiogenic cytokines. Single cell transcriptomics of the bone marrow niche revealed that the reduced monocytosis in diabetic KO mice is a result of impaired hematopoiesis with increased CXCR4 signaling in bone marrow Lineage-Sca1+Kit+ (LSK) cells. Exogenous Ly6Chi monocytes from non-diabetic KO mice rescued the impaired revascularization in ischemic limbs of diabetic KO mice. Increased Cxcr4 expression is mediated by the novel miR-181 target, Plac8. Taken together, MiR-181a/b is a putative mediator of diabetic CLI and contributes to alterations in hematopoiesis, monocytosis, and macrophage polarization.