Circulating inflammatory monocytes oppose microglia and contribute to cone cell death in retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) is an intractable inherited disease that primarily affects the rods through gene mutations followed by secondary cone degeneration. This cone-related dysfunction can lead to impairment of daily life activities, and ultimately blindness in patients with RP. Paradoxically, microglial neuroinflammation contributes to both protection against and progression of RP, but it is unclear which population(s)— tissue-resident microglia and/or peripheral monocyte-derived macrophages (mφ)— are implicated in the progression of the disease. Here, we show that circulating blood inflammatory monocytes (IMo) are key effector cells that mediate cone cell death in RP. Attenuation of IMo and peripherally engrafted mφ by Ccl2 deficiency or immune modulation via intravenous nanoparticle treatment suppressed cone cell death in rd10 mice, an animal model of RP. In contrast, the depletion of resident microglia by a colony-stimulating factor 1 receptor inhibitor exacerbated cone cell death in the same model. In human patients with RP, IMo was increased and correlated with disease progression. These results suggest that peripheral IMo is a potential target to delay cone cell death and prevent blindness in RP.

SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process

“…The role of microglia in photoreceptor degenerations is still controversial. Funatsu J et al [ 30 ] reported that the depletion of resident microglia exacerbated cone cell death in rd10 mice. On the other hand, some researchers have shown that the increase in inflammation mediated by activated microglia is responsible for the pathogenesis and progression of AMD [ 25 , 26 ].…”

“…In addition, CCR2 expression was not detected in cultured Müller cells, although its expression was markedly increased in the LD-retina, which was inhibited by SIG-1451 administration ( Figure 4 D). Ma W et al reported that the gene expression of chemotactic cytokines and cell adhesion molecules in RPE cells was altered by co-culture of activated microglia and that mRNA expression of CCL2 in the RPE cells was significantly increased by co-culture with activated microglia [ 30 ]. Retinal microglia translocate into the outer retina [ 35 ] and accumulate in the subretinal space [ 36 ] under conditions of advanced age and photoreceptor injury.…”

SIG-1451, A Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Inhibiting Microglial Activation

“…In addition, CCR2 expression was not detected in cultured Müller cells, although its expression was markedly increased in the LD-retina, which was inhibited by SIG-1451 administration (Figure 4D). Ma W et al reported that the gene expression of chemotactic cytokines and cell adhesion molecules in RPE cells was altered by co-culture of activated microglia and that mRNA expression of CCL2 in the RPE cells was significantly increased by co-culture with activated microglia [30]. Retinal microglia translocate into the outer retina [35] and accumulate in the subretinal space [36] under conditions of advanced age and photoreceptor injury.…”

In vitro Model Systems for Studies Into Retinal Neuroprotection

“…Microglial Cell Lines. The role of microglial cells in retinal degenerative diseases appears ambiguous, but the general consensus seems to be that these cells are mostly involved in secondary pathologies rather than the primary changes causing IRD (Sancho-Pelluz et al, 2008;Ferrer-Martin et al, 2015;Funatsu et al, 2022). Nevertheless, the relatively recently introduced BV2 and MG5 microglial cell lines may provide new attractive opportunities for studying microglial properties and the possible roles of these cells in photoreceptor degeneration (Chumsakul et al, 2020;Ozaki et al, 2022).…”