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.

• Authors: Antonio Citro, Andrea Valle, Elisa Cantarelli, Alessia Mercalli, Silvia Pellegrini, Daniela Liberati, Luisa Daffonchio, Olga Kastsiuchenka, Pier Adelchi Ruffini, Manuela Battaglia, Marcello Allegretti, Lorenzo Piemonti
• Journal: Diabetes (Diabetes) Vol. 64 Issue 4 Pg. 1329-40 (Apr 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 25315007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Receptors, Interleukin-8A
• Receptors, Interleukin-8B
• Sulfonamides
• reparixin

Topics

• Animals
• Diabetes Mellitus, Experimental (drug therapy, metabolism)
• Diabetes Mellitus, Type 1 (drug therapy, metabolism)
• Islets of Langerhans (drug effects, metabolism)
• Mice
• Mice, Inbred NOD
• Receptors, Interleukin-8A (antagonists & inhibitors)
• Receptors, Interleukin-8B (antagonists & inhibitors)
• Sulfonamides (pharmacology, therapeutic use)