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Mesenchymal Stem Cells Regulate Microglial Polarization via Inhibition of the HMGB1/TLR4 Signaling Pathway in Diabetic Retinopathy

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Abstract

Diabetic retinopathy (DR) is recognized as the most prevalent retinal degenerative disorder. Inflammatory response usually precedes microvascular alteration and is the primary factor of diabetic retinopathy. Activated microglia express many pro-inflammatory cytokines that exacerbate retina inflammation and disruption. In the present study, we found that MSCs alleviated blood–retina barrier (BRB) breakdown in diabetic rats, as evidenced by reduced retinal edema, decreased vascular leakage, and increased occludin expression. The MSC-treated retinal microglia exhibited reduced expression of M1-phenotype markers in the diabetic rats, including inducible nitric oxide synthase (iNOS), CD16, and pro-inflammatory cytokines. On the other hand, MSCs increased the expression of M2-phenotype markers, such as arginase-1 (Arg-1), CD206, and anti-inflammatory cytokines. HMGB1/TLR4 signaling pathway is activated in DR and inhibited after MSC treatment. Consistent with in vivo evidence, MSCs drove BV2 microglia toward M2 phenotype in vitro. Overexpression of HMGB1 in microglia reversed the effects of MSC treatment, suggesting HMGB1/TLR4 pathway is necessary for MSCs’ regulatory effects on microglia polarization. Collectively, MSCs exert beneficial effects on DR by polarizing microglia from M1 toward M2 phenotype via inhibiting the HMGB1/TLR4 signaling pathway.

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Abbreviations

MSCs:

Mesenchymal stem cells

DR:

Diabetic retinopathy

AGEs:

Advanced glycation end products

BRB:

Blood–retina barrier

HMGB1:

High mobility group box 1

TLR4:

Toll-like receptor 4

STZ:

Streptozotocin

NFL:

Nerve fiber layer

IPL:

Inner plexiform layer

OPL:

Outer plexiform layer

GCL:

Ganglion cell layer

INL:

Inner nuclear layer

ONL:

Outer nuclear layer

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Funding

This work was supported by the National Natural Science Foundation of China (NSFC) (grant nos. 81970062 and 81770061 to GY).

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Authors and Affiliations

  1. Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Jun Tong, Yueqin Chen, Hairong Xie, Xinyu Zheng & Zhenggao Xie

  2. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Genhong Yao & Lingyun Sun

  3. Department of Ophthalmology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Jun Tong & Zhenping Huang

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  1. Jun Tong
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Contributions

TJ and CY contributed to collection of data, data analysis, and interpretation. TJ, XH, and ZX performed the whole experimental work. TJ contributed to manuscript writing. YG, SL, and XZ contributed to conception and design, financial support, and final approval of the manuscript. The authors read and approved the final manuscript.

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Correspondence to Lingyun Sun, Zhenping Huang or Zhenggao Xie.

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Tong, J., Yao, G., Chen, Y. et al. Mesenchymal Stem Cells Regulate Microglial Polarization via Inhibition of the HMGB1/TLR4 Signaling Pathway in Diabetic Retinopathy. Inflammation (2024). https://doi.org/10.1007/s10753-024-02005-6

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