CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

Abstract

Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, noncompetitive allosteric inhibitors, were used to pharmacologically blockade CXCR1/2. Transient blockade of said receptors was effective in preventing inflammation-mediated damage in MLD-STZ and in preventing and reversing diabetes in NOD mice. Blockade of CXCR1/2 was associated with inhibition of insulitis and modification of leukocytes distribution in blood, spleen, bone marrow, and lymph nodes. Among leukocytes, CXCR2+ myeloid cells were the most decreased subpopulations. Together these results identify CXCR1/2 chemokine receptors as “master regulators” of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving residual β-cells holds the potential to make a significant change in the approach to management of human T1D.

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

“…This induces insulitis in which macrophage-derived proinflammatory cytokines cause beta cell death [56]. Although this model is not dependent on T and B cells and thus differs from Type 1 diabetes in humans, it is commonly used in preventative strategies, especially those targeting chemokines [57] or nitric oxide induced beta cell death [58]. This model is often used in addition to a spontaneous autoimmune model as additional evidence in preventative strategies.…”

Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)

“…Importantly, this activity can be therapeutically interfered with using the CXCR1/2 antagonist reparixin (39,43), thus hinting at a potential cancer immunotherapy approach. This was also seen in experiments showing the effect of reparixin at reducing the numbers of GrMDSC in CT26GM tumors implanted in immunocompetent mice.…”

“…Reparixin is a described pharmacological inhibitor of CXCR1 and CXCR2 (39,43). Injection of this compound into mice around the time of IL8 gene transfer almost completely abrogated the attraction of MDSC to the liver (Fig.…”

Senescence-associated inflammatory responses: aging and cancer perspectives

“…There are several JAK inhibitors in clinical use, mostly for treatment of myeloproliferative diseases or rheumatoid arthritis [119][120][121]. An inhibitor of the IL-8 receptor C-X-C chemokine receptor type 2 (CXCR2), reparixin [122], is currently Figure 2. Blocking senescence via targeting immune and inflammatory pathways.…”