CD44 Drives M1 Macrophage Polarization in Diabetic Retinopathy

Abstract

Purpose

Diabetic retinopathy is a typical complication of diabetes, which can facilitate the risk of blindness in severe cases. We sought to determine the function of CD44 in inflammatory responses of human retinal microvascular endothelial cells (HRMECs) and macrophage polarization during diabetic retinopathy (DR).

Methods

The hub genes were tested based on two datasets from the Gene Expression Omnibus database. Gene Ontology and pathway enrichment analysis was conducted on the base of differentially expressed genes (DEGs). The infiltration score and infiltration of the immune cells were assessed, and the link between key genes and macrophages was analyzed. The role of CD44 in HRMECs and macrophage polarization was determined by quantitative reverse transcription polymerase chain reaction, western blot, cell counting kit-8, Enzyme-linked immunosorbent assay, flow cytometry, and immunofluorescence.

Results

DEGs were enriched in several pathways linked to DR, such as cellular response to retinoic acid, retinol metabolic process, retina homeostasis, PI3K-AKT signaling pathway, and leukocyte transendothelial migration. A total of 144 DEGs were identified by up-regulation both in GSE102485 and GSE160306. Moreover, the infiltration of macrophages was greater in the DR group than that in the control group. We highlighted an obvious increase in the expression of CD44 and CD86 in patients with DR, and distinct positive associations were found between levels of macrophages and levels of CD44 and CD86. Furthermore, CD44 expression was substantially increased in HRMECs under high glucose (HG) conditions and CD44 knockdown markedly inhibited HG-induced inflammatory responses of HRMECs. HG-induced HRMECs remarkably influenced M1 polarization of macrophages, but CD44 knockdown significantly nullified this effect.

Conclusions

CD44 influenced the advancement of DR via meditating M1 polarization of macrophages. Our findings could enhance the understanding of the mechanism of DR, which might offer a therapeutic target for DR patients.

Keywords:

• CD44
• human retinal microvascular endothelial cells
• M1 macrophage
• diabetic retinopathy
• inflammatory response

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by Key Laboratory of Guangdong Higher Education Institutes (No.2021KSYS009) and Guangzhou Key Laboratory of Biological Targeting Diagnosis and Therapy (No.202201020379).