The Importance of the CXCL12/CXCR4 Axis in Therapeutic Approaches to Diabetes Mellitus Attenuation

Abstract

The pleiotropic chemokine (C–X–C motif) ligand 12 (CXCL12) has emerged as a crucial player in several diseases. The role of CXCL12 in diabetes promotion and progression remains elusive due to its multiple functions and the overwhelming complexity of diabetes. Diabetes is a metabolic disorder resulting from a failure in glucose regulation due to β-cell loss and/or dysfunction. In view of its ability to stimulate the regeneration, proliferation, and survival of β-cells, as well as its capacity to sustain local immune-isolation, CXCL12 has been considered in approaches aimed at attenuating type 1 diabetes. However, a note of caution emerges from examinations of the involvement of CXCL12 in the development of diabetes and its complications, as research data indicate that CXCL12 displays effects that range from protective to detrimental. Therefore, as a beneficial effect of CXCL12 in one process could have deleterious consequences in another, a more complete understanding of CXCL12 effects, in particular its functioning in the cellular microenvironment, is essential before CXCL12 can be considered in therapies for diabetes treatment.

Absence of PARP‐1 affects Cxcl12 expression by increasing DNA demethylation

“…CXCL12 is a potent chemoattractant involved in angiogenesis, leucocyte trafficking, stem cell homing and in processes including development, cell survival, tissue repair and regeneration. 6 CXCL12 plays an important role in β-cell differentiation, pancreatic islet genesis and in anti-apoptotic/anti-necrotic protection of β-cells from diabetogenic agents. 7,8 Moreover, CXCL12 is as an important player in various diseases (including cancer, inflammatory disorders, atherosclerosis, HIV pathology and diabetes), 9,10 hence the biological significance of methylation-dependent regulation of the Cxcl12 gene.…”

CCL2/MCP-1 and CXCL12/SDF-1 blockade by L-aptamers improve pancreatic islet engraftment and survival in mouse

“…Of note, our findings could be of interest also in the type 2 diabetes (T2D) field. Indeed, due to the strong correlation between inflammation and T2D, several anti‐inflammatory strategies for T2D treatment have been proposed and some have been clinically tested . CXCL12 have been proposed both as an inductor or an inhibitor of several aspects of inflammatory response in T2D and its complications, in which CXCL12 walks a thin line between protective and detrimental effects .…”

“…Indeed, due to the strong correlation between inflammation and T2D, several anti‐inflammatory strategies for T2D treatment have been proposed and some have been clinically tested . CXCL12 have been proposed both as an inductor or an inhibitor of several aspects of inflammatory response in T2D and its complications, in which CXCL12 walks a thin line between protective and detrimental effects . This is extremely important especially in regard to the fact that circulating cytokines such as CCL2 can affect beta cell function and diabetes retinopathy …”

MicroRNA as novel biomarkers and therapeutic targets in diabetic kidney disease: An update

“…Augmented inflammation is a hallmark of diabetes, and this proinflammatory state plays a critical role in the development and progression of DKD . Inflammatory factors such as infiltration of macrophage and inflammatory cytokines and chemokines (MCP‐1, IL‐6, TNF‐α, PAI‐1, CXCR4 etc) can activate myofibroblasts at injury sites in the kidney whilst inducing the differentiation of MCs, glomeruli, and renal tubular epithelial cells into fibroblasts, resulting in enhanced ECM production and deposition, which in turn promote fibrosis …”