M1 Microglia-derived Exosomes Promote Activation of Resting Microglia and Amplifies Proangiogenic Effects through Irf1/miR-155-5p/Socs1 Axis in the Retina

Abstract

Activation of microglia plays a key role in the development of neovascular retinal diseases. Therefore, it is essential to reveal its pathophysiological and molecular mechanisms to interfere with disease progression. Here a publicly available single-cell RNA sequencing dataset is used to identify that intercellular communications from M1 microglia toward M0 microglia are increased in the retinal angiogenesis model via exosomes. Moreover, the results both in vitro and in vivo demonstrate that M1 microglia-derived exosomes promote the activation and enhance the proangiogenic ability of resting microglia. Based on miRNA sequencing of exosomes combined with gene interference, further results show that activated microglia-derived exosomes promoted microglial activation by transmitting polarized signals to M0 microglia via miR-155-5p. Subsequently, miR-155-5p suppresses Socs1 and activates the NFκB pathway, which ultimately causes the inflammatory cascade and amplifies the proangiogenic effect. In addition, upregulated Irf1 drives the expression of miR-155-5p in activated microglia, thus leading to an increase in the tendency of miR-155-5p to be encapsulated by exosomes. Thus, this study elucidates the critical role of intercellular communication among various types of microglia in the complex retinal microenvironment during angiogenesis, and contributes to the novel, targeted, and potential therapeutic strategies for clinical retinal neovascularization.

YY1 Lactylation Aggravates Autoimmune Uveitis by Enhancing Microglial Functions via Inflammatory Genes

“…According to previous studies, IRF1 positively regulates microglial activation, amplifies retinal inflammation, and enhances the migratory abilities of multiple cancer cells. [ 37 , 38 , 39 ] IDO1 was closely related to the enhanced migration and proliferation of cancer cells and participates in several immune and inflammatory diseases. [ 40 , 41 , 42 , 43 ] SEMA4D reportedly activated microglia in neurodegenerative and infectious diseases.…”

Role of Exosomes in the Pathogenesis and Theranostic of Alzheimer’s Disease and Parkinson’s Disease

“…It is notable how the effects of exosomes can vary depending on the cell type from which they originate. Research has shown that exosomes derived from M1 microglial cells can activate quiescent microglial cells towards M1 polarization, leading to the release of pro-inflammatory factors and exacerbating pathological processes [ 52 ]. In AD mice, it has been revealed that Aβ is firstly translocated to MVBs and then to exosomes before being secreted out of neurons and transmitted [ 53 ].…”

Macrophage/microglia polarization for the treatment of diabetic retinopathy

“…The communication between microglial cells has also been investigated. Exosomes produced from activated microglia boost microglial activation by sending polarized signals to M0 microglia via miR-155-5p ( 107 ). Inhibiting suppressor of cytokine signaling 1 and activating the NF-κB pathway, miR-155-5p eventually triggers an inflammatory cascade and intensifies the angiogenesis impact ( 107 ).…”

“…Exosomes produced from activated microglia boost microglial activation by sending polarized signals to M0 microglia via miR-155-5p ( 107 ). Inhibiting suppressor of cytokine signaling 1 and activating the NF-κB pathway, miR-155-5p eventually triggers an inflammatory cascade and intensifies the angiogenesis impact ( 107 ). In addition, studies have been conducted to determine how microglia interact with macroglia like Müller cells and astrocytes.…”