Format

Send to

Choose Destination
Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2595-2605. doi: 10.1016/j.bbadis.2019.06.019. Epub 2019 Jul 2.

Exacerbated intestinal inflammation in P2Y6 deficient mice is associated with Th17 activation.

Author information

1
Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec city, QC G1V 0A6, Canada; Centre de recherche du CHU de Québec - Université Laval, Québec city, QC G1V 4G2, Canada.
2
Centre de recherche du CHU de Québec - Université Laval, Québec city, QC G1V 4G2, Canada.
3
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, 6041 Gosselies, Belgium.
4
Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec city, QC G1V 0A6, Canada; Centre de recherche du CHU de Québec - Université Laval, Québec city, QC G1V 4G2, Canada. Electronic address: Jean.Sevigny@crchudequebec.ulaval.ca.

Abstract

Extracellular nucleotides are released as constitutive danger signals by various cell types and activate nucleotide (P2) receptors such as P2Y6 receptor. P2Y6 activation on monocytes induces the secretion of the chemokine CXCL8 which may propagate intestinal inflammation. Also, P2Y6 expression is increased in infiltrating T cells of Crohn's disease patients. As inflammatory bowel disease (IBD) is associated with immune cell recruitment, we hypothesised that P2Y6 would participate to the establishment of inflammation in this disease. To address this, we used P2Y6 deficient (P2ry6--/-) mice in the dextran sodium sulfate (DSS) murine model of IBD. In disagreement with our hypothesis, P2Y6 deficient mice were more susceptible to inflammation induced by DSS than WT mice. DSS treated-P2ry6-/- mice showed increased histological damage and increased neutrophil and macrophage infiltration that correlated with increased mRNA levels of the chemokines KC and MCP-1. DSS treated-P2ry6-/- mice exhibited also higher levels of Th17/Th1 lymphocytes in their colon which correlated with increased levels of IFN-γ and IL-17A in the sera as well as increased mRNA levels of IFN-γ, IL-17A, IL-6, IL-23 and IL-1β in P2ry6-/- colons. This inflammation was also accompanied by a decreased cell proliferation and goblet cell number. Importantly, injection of anti-IL-17 intraperitoneally partially protected P2ry6-/- mice from DSS-induced colitis. Taken together, in the absence of P2Y6, an exacerbated intestinal inflammation to DSS was observed which correlated with increased recruitment of Th17/Th1 lymphocytes. These data suggest a protective role of P2Y6 expressed on leukocytes in intestinal inflammation.

KEYWORDS:

Colitis; P2Y(6) receptor; Th17/Th1 lymphocytes

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center