Disease-associated microglial activation prevents photoreceptor degeneration by suppressing the accumulation of cell debris and neutrophils in degenerating rat retinas

Abstract

Retinitis pigmentosa initially presents as night blindness owing to defects in rods, and the secondary degeneration of cones ultimately leads to blindness. Previous studies have identified active roles of microglia in the pathogenesis of photoreceptor degeneration in RP. However, the contribution of microglia to photoreceptor degeneration remains controversial, partly due to limited knowledge of microglial phenotypes during RP. Rationale: In this study, we investigated the pathways of microglial activation and its contribution to photoreceptor degeneration in RP. Methods: A classic RP model, Royal College of Surgeons rat, was used to explore the process of microglial activation during the development of RP. An inhibitor of colony-stimulating factor 1 receptor (PLX3397) was fed to RCS rats for sustained ablation of microglia. Immunohistochemistry, flow cytometry, RT-qPCR, electroretinography and RNA-Seq were used to investigate the mechanisms by which activated microglia influenced photoreceptor degeneration. Results: Microglia were gradually activated to disease-associated microglia in the photoreceptor layers of RCS rats. Sustained treatment with PLX3397 ablated most of the disease-associated microglia and aggravated photoreceptor degeneration, including the secondary degeneration of cones, by downregulating the expression of genes associated with photoreceptor function and components and exacerbating the impairment of photoreceptor cell function. Disease-associated microglial activation promoted microglia to engulf apoptotic photoreceptor cell debris and suppressed the increase of infiltrated neutrophils by increasing engulfment and inhibiting CXCL1 secretion by Müller cells, which provided a healthier microenvironment for photoreceptor survival. Conclusions: Our data highlight a key role of disease-associated microglia activation in the suppression of rod and cone degeneration, which reduces secondary damage caused by the accumulation of dead cells and infiltrated neutrophils in the degenerating retina.

TREM2 deficiency in microglia accelerates photoreceptor cell death and immune cell infiltration following retinal detachment

“…TREM2 has been reported to bind lipoproteins, such as ApoE, LDL and CLU/ apoj, which form complexes with Aβ aggregates, facilitating their uptake by microglia [54][55][56]. A group of activated microglial cells with similar gene expression profile was also reported in animal models of retinal degeneration [57]. We observed increased expression of Trem2 and its partner gene Tyrobp at 3 days after RD in the present study.…”

Repopulated retinal microglia promote Müller glia reprogramming and preserve visual function in retinal degenerative mice

“…Additionally, we found that Chx10 + cells increased significantly at the beginning of retinal degeneration in rd10 mice before declining, indicating that the acute response to injury activated the stem cell properties in the retina but failed to repair the retina eventually. In our previous study, we noticed that the microglia phenotype changed according to the development of photoreceptor degeneration in RCS rats 14 . In the present study, the number of Chx10 + cells also fluctuated with microglial clearance and repopulation in the inter group.…”

“…However, in mammals, MG show rapid changes in gene expression at the early stage of retina degeneration before a gradual reversion toward a resting state, ultimately gliosis [11]. In our previous studies, microglia are gradually activated into the intermediate stage before being converted to disease-associated microglia, suggesting that there are different subtypes of microglia at the early and late stages of RP [14]. Accordingly, diverse subtypes of microglia seem to play different roles in determining the fate of endogenous stem cells during different phases of injury/degeneration [15].…”

More than meets the eye: The role of microglia in healthy and diseased retina

“…However, a recent work has challenged this view by indicating a protective effect of microglia on cones in the same mouse model ( 174 ), as suggested by the discussed role of microglia in cone homeostasis ( 111 ). In rats, treatments affecting microglia numbers have resulted in reduced visual function, as a consequence of an increased apoptotic rate in retinal neurons ( 172 , 175 ). Partially explaining this protective role, microglia are not only involved in phagocytosis of stressed photoreceptors, but also in refinement and clearance of improper synaptic connections attempted by bipolar cells with remaining photoreceptors.…”