Knockout of Ccr2 alleviates photoreceptor cell death in rodent retina exposed to chronic blue light

Abstract

Age-related macular degeneration (AMD), the leading cause of visual loss after the age of 60 years, is a degenerative retinal disease involving a variety of environmental and hereditary factors. Although it has been implicated that immune system is involved in the disease progression, the exact role that microglia has is still unclear. Here we demonstrated that knockout of Ccr2 gene could alleviate photoreceptor cell death in mice retinas exposed to chronic blue light. In Ccr2−/− mice, a damaged microglia recruitment was shown in retina and this could protect the visual function in electroretinogram and alleviate the photoreceptor apoptosis, which thus helped attenuate the blue light-induced retinopathy. We further found an increased co-location of NLRP3, Iba-1, and IL-1β in fluorescence and a concomitant increased protein expression of NLRP3, caspase-1, and IL-1β in western blotting in chronic blue light-induced retinopathy. Moreover, the activation of microglia and their cellular NLRP3 inflammasomes occurred as an earlier step before the structural and functional damage of the mice retinas, which collectively supported that microglial NLRP3 inflammasome might be the key to the chronic blue light-induced retinopathy.

Monocyte infiltration rather than microglia proliferation dominates the early immune response to rapid photoreceptor degeneration

“…Thus, despite the large, transient increase in CCL2 expression by Müller cells and evidence that blocking the CCL2-CCR2 signaling reduced the influx of CD45 high cells, neurodegeneration proceeded unabated. Unlike other retinal damage studies in which monocytes exacerbate degeneration [14,37,38], our results demonstrate that monocyte infiltration does not necessarily further harm or control the rate of neurodegeneration.…”

“…The loss of photoreceptors in Arr1 −/− mice occurs at light levels that do not cause photolytic damage (75-200 lx, undilated pupils of pigmented mice) or stress the regenerative capacity of the RPE, at least at the early times being considered in this study. This is in contrast to studies that inflicted broader damage, such as Rutar and colleagues [37], who suppressed retinal CCL2 levels with small interfering RNA (siRNA) and found a reduced the number of apoptotic photoreceptors induced by bright light (1000 lx, dilated pupils); Sennlaub and colleagues [14] who knocked out CCL2 and rescued photoreceptor degeneration caused by light stress (4500 lx, dilated pupils); or Hu and colleagues [38] who knocked out CCR2 and found significant structural and functional preservation of the retina after exposure to blue light-induced damage (500 lx, daily for 3 days). The exclusive damage to photoreceptors is presumably why CCL2 is one of only a handful of cytokines that change in the Arr1 −/− at early times ( Fig.…”

Leishmania donovani inhibits inflammasome‐dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2

“…Release of the biologically active IL-1b requires the expression and activation of inflammasome complex, among which the most well-documented one is NLRP3. Activation of the NLRP3 inflammasome complex appears to be dependent on types of cells involved and is effected by a diverse range of stimuli, including microbe-derived products (54), environmental factors (55), and endogenous molecules (56). Reports have indicated that the NLRP3 inflammasome confers protection against L. amazonensis infection in resistant C57BL/6 mice (57), whereas L. major and L. mexicana could significantly inhibit NLRP3 inflammasome function and IL-1b production (58).…”

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…Thus, rats receiving intravitreal injection of CCL2 siRNA showed a markedly decreased phagocyte accumulation and photoreceptor apoptosis after light damage (Rutar et al, ). Similarly, CCR2 knockout mice had much lower photoreceptor demise after chronic blue light exposure (Hu et al, ), less pro‐inflammatory cells and CNV in the laser‐damage model (Robbie et al, ), and fewer subretinal macrophages when immunized with carboxyethylpyrrole‐modified albumin as trigger for oxidative stress (Cruz‐Guilloty et al, ).…”