Adverse effects of CXCR2 deficiency in mice reared under non-gnotobiotic conditions

The family of pro-inflammatory and pro-angiogenic chemokines including Interleukin-8 (IL-8, aka CXCL8) and its homologues (CXCL1,2,3,5,6, and 7) exhibit promiscuous binding and activation of several G-protein-coupled receptors (i.e., CXCR2, CXCR1, and the atypical chemokine receptor (ACKR1)). A high...

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Published in:	Scientific reports Vol. 14; no. 1; pp. 26159 - 22
Main Authors:	Garcia, Maximilian J., Morales, Monica S., Yang, Tzushan S., Holden, Joseph, Bossardet, Olivia L., Palmer, Samuel A., Jhala, Marvarakumari, Priest, Stephen, Namburu, Neeraj, Beatty, Nolan, D’Empaire Salomon, Sariah E., Vancel, Jordan, Wareham, Lauren K., Padovani-Claudio, Dolly Ann
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 30-10-2024 Nature Portfolio
Subjects:	631/1647/334/1874 692/1807/1482 Animals Electroretinography Humanities and Social Sciences Humans Male Mice Mice, Inbred C57BL Mice, Knockout multidisciplinary Receptors, Interleukin-8B - antagonists & inhibitors Receptors, Interleukin-8B - genetics Receptors, Interleukin-8B - metabolism Retina - drug effects Retina - metabolism Retina - pathology Retinal Vessels - drug effects Retinal Vessels - metabolism Retinal Vessels - pathology Science Science (multidisciplinary)
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Summary:	The family of pro-inflammatory and pro-angiogenic chemokines including Interleukin-8 (IL-8, aka CXCL8) and its homologues (CXCL1,2,3,5,6, and 7) exhibit promiscuous binding and activation of several G-protein-coupled receptors (i.e., CXCR2, CXCR1, and the atypical chemokine receptor (ACKR1)). A high proportion of their biological activity is attributed to CXCR2 activation, thus many CXCR2 inhibitors are in clinical trials for several chronic diseases. However, CXCR2 inhibition is often only investigated acutely in these trials or in Cxcr2 −/− mice grown in gnotobiotic conditions. Since humans do not live in germ-free environments, our first goal is to highlight novel retinal and systemic observations in Cxcr2 −/− mice grown in non-gnotobiotic conditions that suggest potential harmful consequences of long-term CXCR2 deficiency or blockade. Beyond confirmation of circulating blood/immune cell-related phenotypes, we report novel findings in Cxcr2 −/− mice including: (1) delayed dye transit to the retinal vasculature, (2) alterations in the density and distribution of retinal vessels, astrocytes and microglia, (3) decreased electroretinogram a- and b-wave amplitudes, (4) reduced visual acuity, and (5) increased polymorphonuclear cell accumulation in vascular lumina abutting venular walls in the retina and in vital non-ocular tissues (lung and liver). Furthermore, PheWAS of CXCR2 CXCR1, and ACKR1 gene variants using data from UK Biobank participants suggest clinical associations with both retinal and vascular disease phenotypes. We conclude that chronic CXCR2 deficiency in mice contributes to functional damage to the retina and that the long-term safety of CXCR1/2 inhibitors designed for chronic use in humans should be explored before clinical adoption to safeguard sight and overall vascular health.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-024-75532-9