Clearance of Microglia as a Treatment for Macular Degeneration – Fight Aging!

Macrophages are innate immune cells of the body, microglia the analogous innate immune cells of the central nervous system. All microglia and most macrophages depend on the function of colony stimulating factor 1 receptor (CSF1R); if this protein or its function are suppressed, the cells die. Following clearance of microglia and macrophages, the populations are restored within a few weeks. If this is carried out in an old animal, the new microglia and macrophages lack some of problems exhibited by the prior population, such as excessive inflammatory signaling, a high burden of cellular senescence, and so forth. There are well established CSF1R inhibitor drugs, such as pexidartinib (PLX3397), and so one can find a number of studies in which neurodegenerative conditions associated with microglial inflammation are improved by temporary clearance followed by repopulation.

Today’s open access paper is an example of this sort of work. The authors provide evidence for clearance of microglia to improve the environment of a damaged retina in a mouse model of age-related macular degeneration. One might compare this to past animal studies in which clearance of microglia improves Alzheimer’s disease and reduces injury following stroke. Beyond that, a considerable weight of evidence links increased numbers of pro-inflammatory microglia, whether activated or senescent, to the onset and progression of neurodegenerative conditions. It is plausible that short-term treatment with pexidartinib or a similar CSF1R inhibitor, avoiding most of the side-effects that accompany long-term use in cancer patients, will prove to be beneficial enough to enter widespread use.

Microglial repopulation restricts ocular inflammation and choroidal neovascularization in mice

Age-related macular degeneration (AMD) is a prevalent, chronic and progressive retinal degenerative disease characterized by an inflammatory response mediated by activated microglia accumulating in the retina. While robust evidence clearly identifies the beneficial effects of microglial repopulation in degenerative neurological diseases, the contributions of repopulating microglia in the retinal degenerative diseases AMD and the potential mechanisms remain incompletely understood.

In this study, we demonstrated that ten days of the CSF1R inhibitor PLX3397 treatment to induce microglial repopulation exacerbated neovascular leakage and angiogenesis formation. We also found that the accumulation of senescent cells in laser sites and treatment with microglial repopulation increased microglial phagocytosis and led to reduced cellular senescence. In addition, new microglia produced less CXCL2 and exhibited lower levels of activation markers than resident microglia, thereby ameliorating leukocyte infiltration and attenuating the inflammatory response in choroidal neovascularization lesions. Our study provides promising insights into the potential of microglial repopulation as a novel, promising therapeutic approach for the treatment of AMD using a mouse model of laser-induced CNV.

Microglia have been implicated to accumulate in the subretinal space, subsequently switching into an activated phenotype and undergoing significant changes in their function in both AMD patients and mouse models. These activated microglia cause the excessive release of inflammatory mediators and a prolonged inflammatory response, which may result in the growth of neovascular lesions and further tissue damage. As microglial survival and function are critically dependent upon CSF1R, CSF1R inhibition can effectively deplete microglia. Withdrawal of CSF1R inhibition results in the rapid repopulation of the whole retina with naïve microglia. Now that microglial activation in CNV has been identified as a symptom of inflammatory damage which in turn exacerbates retinal degeneration, it is plausible to hypothesize that the replacement of these overactivated microglia with new microglia resembling nonreactive homeostatic microglia may relieve the inflammatory response and promote retinal tissue repair in AMD.