Abstract
Microglia activation is recognized as the hallmark of neuroinflammation. However, the activation profile and phenotype changes of microglia during the process of retinal degeneration are poorly understood. This study aimed to elucidate the time-spatial pattern of microglia distribution and characterize the polarized phenotype of activated microglia during retinal neuroinflammation and degeneration in rd1 (Pde6βrd1/rd1) mice, the classic model of inherited retinal degeneration. Retinae of rd1 mice at different postnatal days (P7, P14, P21, P28, P56, and P180) were prepared for further analysis. We found most CD11b+ or IBA1+ microglia expressed Ki-67 and CD68 in rd1 mice and these cells migrated toward the layer of degenerative photoreceptors at the rapid rods degeneration phase from P14 to P28. These microglia exhibited typical ameboid activated shape with round bodies and scarce dendrites, while at late phase at P180, they displayed resting ramified morphology with elongated dendrites. Flow cytometry revealed that the percentage of CD86+CD206- M1 microglia increased markedly in rd1 retinae, however, no significant change was observed in CD206+CD86- M2 microglia. Interestingly, CD86+CD206+ microglia, an intermediate state between the two extremes of M1 and M2, increased markedly at the rapid rods degeneration phase. The immunofluorescence images revealed that microglia in rd1 mice highly expressed M1 markers including CD16/32, CD86, and CD40. In addition, increased expression of pro-inflammatory cytokines (TNF-α, IL-6, and CCL2) was observed in rd1 mice. Our findings unfolded a panorama for the first time that microglia conducted distinctive behaviors with the progression of retinal degeneration in rd1 mice. Microglia is activated and particularly polarized to a pro-inflammatory M1 phenotype at the rapid rods degenerative phase, suggesting that the involvement of M1 microglia in the retinal neuroinflammation and degeneration. Most microglia adopted an intermediate polarization “M1½” state in rd1, revealing that microglia orchestrated a complicated continuous spectrum in degenerative retina.
Highlights
Retinitis pigmentosa (RP) is one of the main causes of severe blindness worldwide in 20–64 year olds, in the young
Microglia have been reported to be activated with morphological changes in response to various insults, which contribute to many neurodegenerative diseases (Colonna and Butovsky, 2017; Liddelow et al, 2017)
To elucidate the activation status of microglia in rd1 mice of inherited retinal degeneration, we collected retinae from these mice at different ages and analyzed the amount and morphology of microglia using IBA1 immunostaining on retinal whole-mounts to detect the microglia morphology
Summary
Retinitis pigmentosa (RP) is one of the main causes of severe blindness worldwide in 20–64 year olds, in the young. It is characterized by the progressive death of photoreceptors, leading to visual impairment (Wright et al, 2010). Novel therapies have been advanced greatly in recent years, it is still incurable at present. Microglia Polarization in rd Mice explored, such as genetic mutations, autophagy deficiency, and neuroinflammation. Sustained inflammation could contribute to the pathological loss of photoreceptor cells in RP and autophagy is implicated as a protective mechanism to resolve neuroinflammation (Cooper et al, 2013; Leinonen et al, 2017). Modulation of retinal inflammatory reaction might be a potential intervention for retinal degeneration (Yoshida et al, 2013a,b)
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