The Anti-Inflammatory Effects of CXCR5 in the Mice Retina following Ischemia-Reperfusion Injury

Abstract

Object. Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many ophthalmic diseases; there are no effective therapeutic approaches available currently. Increasing evidence indicates that microglia mediated neuroinflammation plays an important role in the retinal I/R injury. In this study, we aimed to investigate the roles of chemokine receptor CXCR5 in the pathological process of retinal I/R injury model. Method. Retinal I/R injury model was established in CXCR5 knockout and wild mice by the acute elevation of intraocular pressure (AOH) for 60 minutes, and the eyes were harvested for further analyses. The cellular location of CXCR5 was detected by immunofluorescence staining; the expressions of CXCR5 and CXCL13 after I/R injury were analyzed by quantitative RT-PCR. The retinal microglia were detected as stained for Iba1 (+). Leakage of inflammatory cells was observed on the H&E stained cryosections. The protein expression and quantification of zonula occludens (ZO-1) were determined by Western blotting and densitometry. Capillary degeneration was identified on the intact retinal vasculatures prepared by trypsin digestion. Results. The number of activated microglia marked by Iba1 antibody in the retina was increased after retinal I/R injury in both KO and WT mice, more significant in KO mice. The leakage of inflammatory cells was observed largely at 2 days after injury, but there was no or little leakage at 7 days. The number of inflammatory cells (mainly neutrophils) was greater in CXCR5 KO mice than in WT mice, mainly located under internal limiting membrane. CXCR5 deficiency led to more ZO-1 degradation in CXCR5 KO mice compared to C57BL6 WT mice 2 days after reperfusion. The cellular capillaries were also significantly increased in the KO mice compared to the WT mice. Conclusion. Our findings suggest that the chemokine receptor CXCR5 may protect retina from ischemia-reperfusion injury by its anti-inflammatory effects. Thus, CXCR5 may be a promising therapeutic target for the treatment of retinal I/R injury.

Chemokine CXCL13 acts via CXCR5-ERK signaling in hippocampus to induce perioperative neurocognitive disorders in surgically treated mice

“…Previous studies showed that CXCR5 −/− mice have more immature neurons in the dentate gyrus, an increase in baseline locomotor activity, and decreased anxiety-like behavior [ 39 ]. CXCR5 −/− mice may also develop retinal degeneration with pathophysiological changes, such as activation of microglia and accumulation of inflammatory cells, loss of ZO-1 indicative of impaired blood-retinal barrier function after ischemia-reperfusion injury [ 51 ]. These changes could conceivably produce major impact on learning and memory, and thus bias the results in the current study.…”

Transcriptome-Wide Analysis of CXCR5 Deficient Retinal Pigment Epithelial (RPE) Cells Reveals Molecular Signatures of RPE Homeostasis

“…Previous studies found that deficiency of CXCR5 leads to abnormalities in the RPE and with the presence of AMD-like phenotypes in mice [5,8,9]. The findings suggest that CXCR5 plays a protective role in RPE cells.…”

“…The RPE cells play a crucial role in the survival and function of the neural retina by maintaining ionic homeostasis at the subretinal space, prevent access of blood components to the neural retina and autoimmune response, which are in part attributed to the formation of the outer blood-retina barrier (BRB) [12]. Our previous studies suggested that CXCR5 signaling plays a protective role in the integrity of RPE cells to prevent the development of AMD-like pathological phenotypes in mice [5,8,9]. Further evidence supports the notion that CXCR5 is required for the homeostasis of RPE cells ( Figure 1A, B, and unpublished data).…”

“…In summary, our investigation reveals that deficiency of CXCR5 abrogates CXCL13/CXCR5 signaling and this alters the normal PI3K-Akt signaling pathway, FoxO signaling pathway, mTOR signaling pathway, focal adhesion, endocytosis, ubiquitin-mediated proteolysis, TNF-alpha NF-kB signaling pathway, adipogenesis genes, p53 signaling, Ras pathway, autophagy, epithelial-mesenchymal transition (EMT), and mitochondrial pathways, leading to dysregulated RPE functioning, which may result in retinal degeneration that is observed in vivo [5,8,9]. The complex interplay between dysfunctional RPE, microglia, and immune cells, along with impaired blood-retinal barrier, requires further investigations.…”

“…There are about 20-30 chemokine receptors in the mammalian genome, including humans. Chemokine receptors are hypothesized to be essential for the pathogenesis of AMD, as they regulate the migration of immune and inflammatory cells, which contributes to the initiation and development of AMD [4,5]. The C-X-C motif chemokine receptor 5 (CXCR5), a chemokine transmembrane receptor, belongs to the C-X-C chemokine receptor family.…”