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Super‐MANF to the Rescue: Immunomodulation Improves Retinal Repair and Regenerative Cell Therapy

Interactions between damaged tissues and immune cells are increasingly being appreciated for their consequences on tissue repair. Neves et al demonstrate, in Drosophila and in mice, that damaged epithelial cells produce platelet-derived growth factor (Pvf-1/PDGF) that signals to innate immune cells to produce a conserved immunomodulatory factor, mesencephalic astrocyte-derived neurotrophic factor (MANF), that promotes macrophage alternative activation and tissue repair. Similar to how organ transplantation serves as a cure for many end-stage organ diseases, regenerative therapies utilizing cell replacement could successfully treat numerous age-related degenerative diseases. As widespread use of transplantation was first limited by the hostile environment into which genetically distinct organs were transplanted (therefore, donor–recipient matching and immunosuppression were employed to dampen the host immune response and make the environment less hostile), so have regenerative therapies been limited in their success by unfavorable tissue microenvironments in degenerating tissues. Neves and colleagues set out to identify an approach to modulate the immune system to make degenerating tissue microenvironments more hospitable for cell replacement therapies. The authors performed an RNA-sequencing study in Drosophila to identify factors in macrophage-like cells called hemocytes that supported tissue repair in response to ultraviolet (UV) damage, as hemocyte-deficient fly eyes cannot recover from UV injury. MANF was identified downstream of PDGF signaling and facilitated retinal repair. Hemocyte-derived MANF signaled in an autocrine fashion to cause alternative activation, leading to arginase production, a characteristic molecule of alternatively activated macrophages in mammals. In mice and humans, macrophages are frequently subdivided into two classes, those classically activated by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) called M1, that promote inflammation and pathogen clearance, and those alternatively activated by IL-4 called M2, which promote tissue repair. These data suggest MANF may be an additional factor capable of programming M2-like cells. Extending their studies to mice, the authors discovered increased MANF-expressing CD11b+ macrophages in the eye post–light SUMMARY AND ANALYSIS Watch LITERATURE