NOD1 deficiency ameliorates the progression of diabetic retinopathy by modulating bone marrow–retina crosstalk

Abstract

Background Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) plays a pivotal role in inducing metabolic inflammation in diabetes. Additionally, the NOD1 ligand disrupts the equilibrium of bone marrow-derived hematopoietic stem/progenitor cells, a process that has immense significance in the development of diabetic retinopathy (DR). We hypothesized that NOD1 depletion impedes the advancement of DR by resolving bone marrow dysfunction. Methods We generated NOD1−/−-Akita double-mutant mice and chimeric mice with hematopoietic-specific NOD1 depletion to study the role of NOD1 in the bone marrow–retina axis. Results Elevated circulating NOD1 activators were observed in Akita mice after 6 months of diabetes. NOD1 depletion partially restored diabetes-induced structural changes and retinal electrical responses in NOD1−/−-Akita mice. Loss of NOD1 significantly ameliorated the progression of diabetic retinal vascular degeneration, as determined by acellular capillary quantification. The preventive effect of NOD1 depletion on DR is linked to bone marrow phenotype alterations, including a restored HSC pool and a shift in hematopoiesis toward myelopoiesis. We also generated chimeric mice with hematopoietic-specific NOD1 ablation, and the results further indicated that NOD1 had a protective effect against DR. Mechanistically, loss of hematopoietic NOD1 resulted in reduced bone marrow-derived macrophage infiltration and decreased CXCL1 and CXCL2 secretion within the retina, subsequently leading to diminished neutrophil chemoattraction and NETosis. Conclusions The results of our study unveil, for the first time, the critical role of NOD1 as a trigger for a hematopoietic imbalance toward myelopoiesis and local retinal inflammation, culminating in DR progression. Targeting NOD1 in bone marrow may be a potential strategy for the prevention and treatment of DR.

1. Introduction

Diabetic retinopathy (DR) is a prominent microvascular complication of diabetes and ranks as the primary cause of blindness among working-age adults in developed nations [1]. Present treatments include intravitreal anti-VEGF injections, laser photocoagulation, and vitrectomy [2]. These therapeutic choices primarily address advanced stages of DR once vision is compromised, potentially lacking universal efficacy and offering limited options during the early phases of the condition. Consequently, it has become imperative to delve deeper into the cellular and molecular mechanisms underpinning the pathobiology of DR progression.

Accumulating evidence suggests that diabetes compromises the integrity of the intestinal barrier, facilitating the translocation of microorganisms, their metabolites, and pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS) and peptidoglycan (PGN), into the bloodstream [3]. PAMPs and their receptors have garnered attention with regard to diabetes pathogenesis due to their capacity to incite an immune response and provoke chronic low-grade inflammation upon entry into circulation, potentially culminating in insulin resistance [4]. Numerous studies underscore the association between elevated circulating LPS, a well-studied PAMP, and the advancement of diabetic microvascular complications [5]. Both chronic and acute administration of LPS in animal models mimics the pathological hallmarks of diabetic retinopathy (DR) or exacerbates existing retinopathy in diabetes by targeting Toll-like receptor 4 (TLR4) [6, 7]. Interestingly, our recent investigations have identified the accumulation of another type of PAMP, PGN, in the plasma of both type 1 and type 2 diabetic patients as well as in diabetic mouse models [8, 9]. Furthermore, nucleotide-binding oligomerization domain-containing protein 1 (NOD1), a widely expressed intracellular receptor for PGN, has been recognized as a pivotal sensor in triggering metabolic inflammation and insulin resistance in diabetes [10]. However