Adverse effects of CXCR2 deficiency in mice reared under non-gnotobiotic conditions
Maximilian J Garcia1, Monica S Morales1, Tzushan S Yang2
1Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute/Vanderbilt University Medical Center, 2311 Pierce Avenue, Nashville, TN, USA.
Abstract:
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.
Insights
Long-term deficiency in CXCR2 (C-X-C motif chemokine receptor 2) in mice causes retinal damage and altered vascular function. Further research is needed to assess the safety of CXCR2 inhibitors for chronic human use.
Area of Science:
- Immunology
- Ophthalmology
- Pharmacology
Background:
- Pro-inflammatory chemokines like Interleukin-8 (IL-8) activate G-protein-coupled receptors, notably CXCR2.
- CXCR2 plays a significant role in biological activity, leading to its inhibition in clinical trials for chronic diseases.
- Current research often overlooks long-term CXCR2 inhibition effects in non-germ-free conditions.
Purpose of the Study:
- To investigate novel retinal and systemic consequences of long-term CXCR2 deficiency in mice under non-gnotobiotic conditions.
- To explore potential harmful effects of chronic CXCR2 blockade.
- To assess clinical associations of CXCR2, CXCR1, and ACKR1 gene variants with retinal and vascular diseases.
Main Methods:
- Phenotypic analysis of Cxcr2 knockout (Cxcr2-/-) mice under non-gnotobiotic conditions.
- Assessment of retinal vasculature, astrocytes, microglia, and visual function (electroretinogram, visual acuity).
- Phenome-wide association studies (PheWAS) using UK Biobank data for CXCR2, CXCR1, and ACKR1 gene variants.
Main Results:
- Cxcr2-/- mice exhibited delayed retinal dye transit, altered retinal vessel and cell distribution, and reduced electroretinogram amplitudes.
- Visual acuity was decreased, and polymorphonuclear cell accumulation increased in retinal and systemic tissues.
- PheWAS indicated clinical associations between CXCR2, CXCR1, ACKR1 variants and retinal/vascular disease phenotypes.
Conclusions:
- Chronic CXCR2 deficiency in mice leads to functional retinal damage and systemic vascular changes.
- The long-term safety of CXCR1/2 inhibitors for chronic human use requires thorough investigation to protect vision and vascular health.
