Small extracellular vesicles derived from reactive microglia contribute to retinal neuroinflammation and neurodegeneration

Abstract

Glaucoma is a leading cause of blindness worldwide and is characterized by progressive degeneration of retinal ganglion cells and damage to the optic nerve. Elevated intraocular pressure is a main risk factor. Moreover, chronic neuroinflammation plays an important role in glaucoma. Microglia become reactive when challenged with elevated pressure, releasing cytotoxic factors that contribute to retinal ganglion cell death. We have been reporting that controlling microglia‐mediated neuroinflammation in experimental glaucoma is sufficient to protect retinal ganglion cells from damage.Small extracellular vesicles are constitutively released by most cells and are important vehicles of intercellular communication, conveying lipids, proteins and genetic material. Small extracellular vesicles derived from microglia exposed to elevated pressure trigger a pro‐inflammatory response in microglia, as determined by increased production of proinflammatory cytokines, microglia motility, phagocytosis, and proliferation. These small extracellular vesicles also increase cell death and impact the survival of retinal ganglion cells. The depletion of retinal microglia halt neuroinflammation induced by small extracellular vesicles isolated from microglia at elevated pressure, suggesting that microglial small extracellular vesicles preferentially interact with microglia. Small extracellular vesicles isolated from microglia challenged with elevated pressure are also enriched in proteins associated with inflammatory signalling and RNA processing and in miRNAs that modulate the NF‐kappaB pathway.This route of communication between microglia involving small extracellular vesicles helps to clarify the pathological mechanisms in glaucoma and may open new perspectives for the development of therapies targeting microglia neuroinflammation.Funding: FCT, Portugal (UID/NEU/04539/2019; UIDB/04539/2020; UIDP/04539/2020), COMPETE‐FEDER (FCOMP‐01‐0124‐FEDER‐028417; POCI‐01‐0145‐FEDER‐007440), Centro 2020 Regional Operational Programme (CENTRO‐01‐0145‐FEDER‐000008: BRAINHEALTH2020).