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

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 the multiple low doses (MLD)-streptozotocin (STZ) injection and the NOD mouse models to investigate the potency of CXCR1/2 inhibition to prevent inflammatory- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, non-competitive allosteric inhibitors, were used to obtain the pharmacologic blockade of CXCR1/2. Transient blockade of said receptors was effective in preventing inflammatory-mediated damage in MLD-STZ and in preventing and reverting diabetes in NOD mice. Blockade of CXCR1/2 was associated with insulitis inhibition and modification of leucocytes distribution in blood, spleen, bone marrow and lymph nodes. Among leucocytes, CXCR2 + myeloid cells were the most decreased subpopulations. All together these results propose CXCR1/2 chemokine receptors as “master regulators” of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving the residual β-cells holds the potential to make a significant change in the approach to management of human T1D.