title: 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.affiliation: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy Department of Surgery, University of Pavia, Pavia, Italy.
authors.forename: Antonio
authors.identifier: http://orcid.org/0000-0002-0947-7687
authors.initials: A
authors.lastname: Citro
authors.affiliation: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0002-4764-8336
authors.initials: A
authors.lastname: Valle
authors.affiliation: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elisa
authors.identifier: http://orcid.org/0000-0002-3633-3654
authors.initials: E
authors.lastname: Cantarelli
authors.affiliation: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Mercalli
authors.affiliation: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pellegrini
authors.affiliation: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Liberati
authors.affiliation: Research and Development Department, Dompè Farmaceutici S.p.A, L'Aquila, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Daffonchio
authors.affiliation: Research and Development Department, Dompè Farmaceutici S.p.A, L'Aquila, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Kastsiuchenka
authors.affiliation: Research and Development Department, Dompè Farmaceutici S.p.A, L'Aquila, Italy.
authors.forename: Pier Adelchi
authors.initials: PA
authors.lastname: Ruffini
authors.affiliation: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
authors.affiliation: Research and Development Department, Dompè Farmaceutici S.p.A, L'Aquila, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Allegretti
authors.affiliation: San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy piemonti.lorenzo@hsr.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; C490707:reparixin