CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice

Antonio Citro, Andrea Valle, Elisa Cantarelli, Alessia Mercalli, Silvia Pellegrini, Daniela Liberati, Luisa Daffonchio, Olga Kastsiuchenka, Pier A delchi Ruffini, Manuela Battaglia, Marcello Allegretti, Lorenzo Piemonti

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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.

Original languageEnglish
Pages (from-to)1329-1340
Number of pages12
JournalDiabetes
Volume64
Issue number4
DOIs
Publication statusPublished - Apr 1 2015

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Citro, A., Valle, A., Cantarelli, E., Mercalli, A., Pellegrini, S., Liberati, D., Daffonchio, L., Kastsiuchenka, O., Ruffini, P. A. D., Battaglia, M., Allegretti, M., & Piemonti, L. (2015). CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice. Diabetes, 64(4), 1329-1340. https://doi.org/10.2337/db14-0443