Mononuclear phagocyte clearance in immune- and non-immune-privileged sites. – MACLEAR

Mononuclear phagocytes (MP) comprise a family of cells that include monocyte (Mo), resident macrophages (rMf) such as microglial cells (MC), and monocyte-derived inflammatory macrophages (iMf) that arise during inflammation. Resident Mfs such as MCs survey the local tissue environment, respond to tissue injury and serve as gatekeepers to maintain tissue homeostasis. Inflammatory macrophages derive from monocytes recruited from the blood during tissue insults, and their removal from tissues signs the resolution phase of inflammation. Resolution of inflammation is a crucial step towards return to tissue homeostasis and repair. However, there is a growing list of health conditions in which resolution fails to occur and low-grade chronic inflammation is observed. Our groups have previously studied chronic inflammation in the context of metabolic disease (obesity, atherosclerosis) and age related macular degeneration (AMD). While nonresolving inflammation is not a primary cause of these diseases, it is believed to cause considerable collateral damage, which causes more inflammation, entering a vicious cycle.
We have shown that local death controls macrophage removal during resolution of acute inflammation in peritonitis, refuting the concept that macrophages are dominantly cleared through emigration. However, the molecular mechanisms leading to iMf death during the resolution of acute inflammation are ill defined. They might include a decrease in growth factors and inflammatory cytokines necessary for their survival, an intrinsically programmed maximal life-span of iMfs, or an active induction of apoptosis by other cells, such as natural killer cells recruited in late inflammation for example.
Certain sites of the human body, such as retinal pigment epithelium (RPE), that lines the subretinal space, have strong immunosuppressive capacities and potently induce leukocyte death physiologically. We have recently shown that MPs introduced in the subretinal space quickly undergo apoptosis dependent on FasL expression by the retinal pigment epithelium (RPE). We showed that RPE FasL expression can be diminished by MP-derived IL6 in certain pathologies such as AMD and neurotoxic iMfs accumulate.
We hypothesize that MP clearance in immune privileged tissues and iMf elimination during inflammation resolution in non-immune sites likely share common molecular pathways. The literature, our published and preliminary data suggest that Fas/FasL, TSP-1 and CFH play an important role, but are likely not the only factors to influence apoptosis of MPs. “MACLEAR” proposes to precisely study the resolution phase of acute inflammation in peritonitis and subretinal inflammation in terms of rMf (MC) and iMf populations. We propose to identify the mediators of extrinsically induced MP death by studying RPE-induced MP death as they are likely most evident in an immunosuppressive site. On the other hand, we will study iMfs intrinsic mediators in flow cytometry-sorted iMfs in peritonitis, as they are difficult to isolate in sufficient numbers in subretinal inflammation. Identified extrinsic factors will than be studied in peritonitis resolution and identified intrinsic mechanisms in subretinal inflammation. This approach should enable us to identify the factors (and combination of factors) able to eliminate iMfs and fasten inflammation resolution, and to restore subretinal immunosuppression. The therapeutic feasibility to inhibit chronic inflammation using these mediators will be tested on our models of chronic subretinal inflammation and in murine obesity models. “MACLEAR” holds the promise to develop a therapeutic strategy to induce resolution of chronic inflammation that might be beneficial for patients suffering from diseases such as obesity or AMD.