Immune Cells in Subretinal Wound Healing and Fibrosis

Abstract

The subretinal space is devoid of any immune cells under normal conditions and is an immune privileged site. When photoreceptors and/or retinal pigment epithelial cells suffer from an injury, a wound healing process will be initiated. Retinal microglia and the complement system, as the first line of retinal defense, are activated to participate in the wound healing process. If the injury is severe or persists for a prolonged period, they may fail to heal the damage and circulating immune cells will be summoned leading to chronic inflammation and abnormal wound healing, i.e., subretinal or intraretinal fibrosis, a sight-threatening condition frequently observed in rhematogenous retinal detachment, age-related macular degeneration and recurrent uveoretinitis. Here, we discussed the principles of subretinal wound healing with a strong focus on the conditions whereby the damage is beyond the healing capacity of the retinal defense system and highlighted the roles of circulating immune cells in subretinal wound healing and fibrosis.

Keywords: adaptive immunity; age-related macular degeneration; inflammation; innate immunity; macular fibrosis; proliferative vitroretinopathy; retina.

FIGURE 1

Wound healing in the subretinal space. (A) When the initial insult is mild or one-off, the injury can be promptly rectified by retinal innate immune system (may also be assisted by infiltrating innate immune cells) and the subretinal space returns to homeostasis. If the injury causes a significant number of photoreceptor loss, Müller cells will be activated (may also be transdifferentiated into myofibroblast). Muller cells, myofibroblasts along with ECM proteins produced by them will fill the space left by dead cells forming gliosis without ongoing inflammation (or cold fibrosis). (B) When the insult to photoreceptors or RPE cells persists or is severe, retinal immune system, circulating innate and adaptive immune cells may all participate in the healing process. If the subretinal damage does not involve the ingrowth of new blood vessels, such as in GA and RRD, the damaged photoreceptor/RPE cells may be replaced by active Müller glia (i.e., gliosis) or myofibroblasts transdifferentiated from other cells such as RPE cells or macrophages. In RRD-induced PVR, the wound healing response leads to excessive ECM deposition and the development of subretinal fibrotic membrane; whereas, in GA, the wound is filled with active Muller glia and infiltrating immune cells without excessive ECM deposition and damage area becomes atrophic. In nAMD, new blood vessels are a part of the pathology, and the healing process is accompanied by continued immune cell infiltration and excessive deposition of ECM around the diseased blood vessels and eventually, the development of fibro-vascular membrane.

FIGURE 2

The role of innate and adaptive immune cells in wound healing, organ and subretinal fibrosis. Cells were adopted from BioRender.com.

FIGURE 3

Macrophages/microglia in the subretinal fibrotic lesion. Representative images, and their zoom-in images, of the lesion (left panel) and non-lesion (right panel) area of RPE flat mounts stained for collagen-1, DAPI and F4/80 (A, macrophage marker), CX3CR1 (B, microglial marker), and Iba1 (C, marker for activated microglia and macrophages). Scale bars = 25 μm; Zoom images Scale bars = 10 μm.

FIGURE 4

Innate immune cells in the subretinal fibrotic lesion. Representative images, and their zoom in images, of the lesion (left panel) and non-lesion (right panel) areas of RPE flatmounts stained for collagen-1, DAPI and MHCII (A), Gr-1 (B), CD335/Nkp46 (C). Scale bars = 25 μm; Zoom images Scale bars = 10 μm.