Mononuclear Phagocytes, Inflammation Act as Mediators in AMD


In AMD, early pathogenic changes may be related to immune system responses causing inflammation and subsequent tissue damage resulting from that inflammation.

Xavier Guillonneau, PhD, Institute of Vision

Xavier Guillonneau, PhD

The connections between age-related macular degeneration (AMD), inflammation, and the accumulation of mononuclear phagocytes (MP) in subretinal environments may be more complicated than originally believed.

Published in Progress in Retinal and Eye Research and led by Xavier Guillonneau, PhD, with the Institute of Vision at the Sorbonne in Paris, France, new research discussed multiple risk "cofactors" related to the accumulation of MPs, including nonresolving inflammation and immune system responses as important factors for AMD development, suggesting that AMD treatments should address issues of chronic inflammation triggered by immune response in order to minimize tissue damage and AMD progression in patients.

Currently, the pathomechanisms of AMD can be grouped into 3 sections: The insufficiencies in the choroidal vascular system; the dysfunction of the retinal pigment epithelium (RPE); and chronic inflammation. All of which, "likely all play into the disease development to different degrees in individual patients." MPs play a role in each process by triggering inflammation via monocytes, inflammatory macrophages, dendritic cells (DCs) and microglial cells (MCs), according to the authors.

MPs are present throughout the body, and several types are found in the "posterior segment of the eye," but not in the central photoreceptor cell layer or subretinal space in healthy adults without AMD. This is due in part to the immunosuppressive nature of the retinal environment, Guillonneau and colleagues noted.

This absence of MPs in subretinal space does not hold true for those with AMD, and “a number of studies have observed inflammatory cells, particularly MPs, but also lymphocytes" in subretinal space and neovascular membranes in AMD patients. Those MPs and leukocytes, according to Guillonneau, build up on the RPE in AMD and may be triggering an immunoresponse that exacerbates AMD symptoms on several levels.

While AMD is associated with a pre-activation local MP infiltration of the photoreceptor cells, that accumulation occurs adjacent to the prominent indicators of the condition, suggesting that MPs may play a role in the disease’s pathogenic changes — particularly those associated with geographic atrophy.

Guillonneau and colleagues argue that those early pathogenic changes may be related to immune system responses causing inflammation and subsequent tissue damage resulting from that inflammation.

The article suggested that the eyes of AMD patients may be affected by a lack of "tissue homeostasis" in response to inflammatory reactions and upregulations of inflammatory cytokines. Guillonneau and colleagues wrote that if the inflammatory response is not controlled in AMD, and if tissue homeostasis is not re-established "after the elimination of persistent tissue stress" then the inflammatory response can quickly "become pathogenic and contribute to disease progression." The inability to re-establish tissue homeostasis within retinal spaces can lead to nonresolving inflammation which can lead to tissue damage in a “vicious circle,” wrote Guillonneau.

He argued that, often, this immune system triggered inflammation response is perhaps a response to changes in specific genes, regulatory protein signaling deficiencies, insufficient retinal pigment epithelium signaling abilities, or even decreased the ability of MPs to resolve inflammation resulting from normal light damage in aging eyes.

Guillonneau believes that although MPs might initial trigger inflammation, they also fulfill a role in the "resolution phase of acute inflammation" by attempting to reestablish homeostasis in retinal tissues. MPs have 2 polarized "activation states" in immune responses, the first of which is described as "pro-inflammatory, anti-microbial, anti-angiogenic, potentially neurotoxic" and defined by anti-vascular endothelial growth factor (VEGF) mediators, and the second of which is "anti-inflammatory, promotes phagocytosis, neovascularization and wound healing" characterized by the increased expression of VEGF.

This means that the presence of MPs in subretinal and retinal space cannot be clearly identified as either "good" or "bad" without looking at the details of how those MPs are functioning in that space.

Guillonneau and colleagues pointed out that although AMD risk can be reduced through healthy lifestyle changes in individuals, there are also complex risk factors involving immunity, MPs, and inflammation outside of those lifestyle factors that affect AMD risk.

The article suggested that concentrating on treatment/therapy for AMD which can "inhibit pathogenic MP accumulation" by curbing inflammation, restoring RPE immune suppression and homeostasis may be key to helping "diminish the need for anti-angiogenic therapies" (anti-VEGF) and "stopping GA lesion growth" before it affects visual acuity. Although recent trends in the treatment of AMD center on anti-VEGF therapies, Guillonneau and colleagues seem to suggest that it may be necessary to focus not on these treatments alone, but also on treatment for chronic inflammation associated with AMD.

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