Portal de Periódicos da CAPES

Visualizing the Heterogeneity of Retinal Microglia

2019; Cell Press; Volume: 50; Issue: 3 Linguagem: Inglês

10.1016/j.immuni.2019.02.017

1097-4180

Jonathan B. Lin, Rajendra S. Apte,

Retinal and Optic Conditions

In this issue of Immunity, O'Koren et al., 2019O'Koren E.G. Yu C. Klingeborn M. Wong A.Y. Prigge C.L. Mathew R. Kalnitsky J. Msallam R. Aymeric S. Kay J.N. et al.Microglial Function Is Distinct in Different Anatomical Locations during retinal Homeostasis and Degernation.Immunity. 2019; 50 (this issue): 723-737Scopus (140) Google Scholar report that murine retinal microglia are long lived and are divided into two spatially and functionally distinct niches in the retina. In models of retinal neurodegeneration, retinal microglia migrate to the subretinal space, an inducible disease-associated niche, where they are neuroprotective. In this issue of Immunity, O'Koren et al., 2019O'Koren E.G. Yu C. Klingeborn M. Wong A.Y. Prigge C.L. Mathew R. Kalnitsky J. Msallam R. Aymeric S. Kay J.N. et al.Microglial Function Is Distinct in Different Anatomical Locations during retinal Homeostasis and Degernation.Immunity. 2019; 50 (this issue): 723-737Scopus (140) Google Scholar report that murine retinal microglia are long lived and are divided into two spatially and functionally distinct niches in the retina. In models of retinal neurodegeneration, retinal microglia migrate to the subretinal space, an inducible disease-associated niche, where they are neuroprotective. Mononuclear phagocytes are key cells of the innate immune system and have been well described as playing important roles in the mammalian retina, both in homeostasis and in disease states. However, a major challenge in understanding the role of mononuclear phagocytes in the neurosensory retina is their heterogeneity, as they can arise from multiple lineages, including monocyte-derived macrophages and tissue-resident macrophages such as microglia. It is being increasingly appreciated that these are distinct cell types with important and specialized roles in health and in disease pathogenesis. Although characterizing subtypes of mononuclear phagocytes that are distinguishable by unique molecular signatures has traditionally been challenging due to similarities in their expression of surface markers, new approaches, including fate mapping, have been employed to further our understanding of these distinct cell populations and how they influence retinal neuroinflammation (O'Koren et al., 2016O'Koren E.G. Mathew R. Saban D.R. Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina.Sci. Rep. 2016; 6: 20636Crossref PubMed Scopus (115) Google Scholar). These studies may provide further mechanistic insight into the pathophysiology of retinal neurodegeneration. In this issue of Immunity, O'Koren et al., 2019O'Koren E.G. Yu C. Klingeborn M. Wong A.Y. Prigge C.L. Mathew R. Kalnitsky J. Msallam R. Aymeric S. Kay J.N. et al.Microglial Function Is Distinct in Different Anatomical Locations during retinal Homeostasis and Degernation.Immunity. 2019; 50 (this issue): 723-737Scopus (140) Google Scholar used lineage tracing and single-cell transcriptomics to explore the role of murine retinal microglia in homeostasis and during retinal neurodegeneration. They found that retinal microglia occupy two spatially and functionally distinct niches in the retina under homeostasis and migrate to the subretinal space, an inducible disease-associated niche, under certain disease conditions, where they play a neuroprotective role (Figure 1). The retina is a delicate complex neurovascular structure that is responsible for converting light stimuli into a neuronal signal to be sent to the brain. Light photons are sensed by rod and cone photoreceptors at the posterior aspect of the retina and then transmitted to second-order bipolar cells in the outer plexiform layer (OPL) and subsequently to third-order retinal ganglion cells in the inner plexiform layer (IPL), whose axons form the optic nerve. Microglia are the tissue-resident macrophages of the retina and have been suggested to play important roles in antigen sensing, immune surveillance, and structural integrity. O'Koren et al., 2019O'Koren E.G. Yu C. Klingeborn M. Wong A.Y. Prigge C.L. Mathew R. Kalnitsky J. Msallam R. Aymeric S. Kay J.N. et al.Microglial Function Is Distinct in Different Anatomical Locations during retinal Homeostasis and Degernation.Immunity. 2019; 50 (this issue): 723-737Scopus (140) Google Scholar first demonstrated, using a fate-mapping approach, that microglia in the adult murine retina were indeed derived from yolk-sac progenitors, like microglia found in other parts of the CNS, and that they were long lived for at least one year. Under homeostatic conditions, retinal microglia were localized to two distinct niches: the OPL and the IPL. Unlike OPL microglia, IPL microglia appeared to depend on interleukin-34 (IL-34) secreted from retinal ganglion cells for survival. IL-34 is an alternate ligand of colony-stimulating factor-1 receptor (Csf1r), which has been demonstrated to be important for maintenance of microglia in the adult murine brain. Another difference between IPL and OPL microglia was that the former, but not the latter, provided fine-tuning of visual information via feedback regulation at the level of cone-bipolar-cell axons. Despite this difference in IL-34 dependency, both IPL and OPL microglia migrated to the subretinal space and adhered to the retinal pigment epithelium (RPE) in two models of retinal neurodegeneration: acute, light-induced retinal neurodegeneration and genetic mutant RhoP23H/WT mice that model the human disease of retinitis pigmentosa. This subretinal space is a potential space that exists only in certain disease states because the RPE and retina are normally closely apposed to each other under physiologic conditions. In contrast to microglia, monocyte-derived macrophages were unable to occupy the subretinal space in both models, even when native microglial cells were depleted. Next, O'Koren et al., 2019O'Koren E.G. Yu C. Klingeborn M. Wong A.Y. Prigge C.L. Mathew R. Kalnitsky J. Msallam R. Aymeric S. Kay J.N. et al.Microglial Function Is Distinct in Different Anatomical Locations during retinal Homeostasis and Degernation.Immunity. 2019; 50 (this issue): 723-737Scopus (140) Google Scholar used single-cell RNA sequencing to characterize how the transcriptional profile of retinal microglia changed when they migrated to the subretinal space in the light-induced degeneration model. They found that migrating microglia downregulated homeostatic genes and immune-response-pathway genes, with concomitant upregulation of cell recognition and adhesion-pathway genes, lipid metabolism genes, and antioxidant-pathway genes. These findings suggested that microglia migrating to the subretinal space may be neuroprotective. In support of a neuroprotective role for microglia in the light-induced degeneration model, depletion of microglia led to accumulation of photoreceptor-outer-segment debris, increased pyknotic nuclei in the outer nuclear layer, and alterations in actin morphology indicative of RPE stress. Although more subtle, depletion of microglia in RhoP23H/WT mutant mice also led to more-shortened and more-disorganized outer segments and microvilli disengagement, suggestive of worsened photoreceptor dysfunction. Based on these data, O'Koren et al., 2019O'Koren E.G. Yu C. Klingeborn M. Wong A.Y. Prigge C.L. Mathew R. Kalnitsky J. Msallam R. Aymeric S. Kay J.N. et al.Microglial Function Is Distinct in Different Anatomical Locations during retinal Homeostasis and Degernation.Immunity. 2019; 50 (this issue): 723-737Scopus (140) Google Scholar concluded that retinal microglia play important protective roles in retinal neurodegeneration and may therefore be a potential therapeutic target for blinding diseases. These seminal findings might inform future investigations in macrophage biology and enhance our ability to manipulate these cells for immune-based neuroprotective therapies for retinal neurodegeneration. The most important finding in this work is confirmation that retinal microglia are indeed derived from yolk-sac progenitors and are long lived, similar to microglia found elsewhere in the CNS. Moreover, retinal microglia are layered into two spatially and functionally distinct subpopulations, which have important roles in regulating retinal function, both in homeostasis through visual-information processing and in disease by migrating to the subretinal space and protecting the RPE from damage. These findings illuminate our understanding of the intricate interactions between retinal neurons and immune cells and may have potential implications beyond the retina in neurodegenerative diseases in which microglia have been shown to play essential roles in regulating neuroinflammation. One intriguing finding of this study was that migration of microglia to the subretinal space was protective in murine models of retinal neurodegeneration. These findings are in contrast with prior work in which phagocytosis of living photoreceptors by microglia and microglial production of proinflammatory cytokines contributed to cell death in the rd10 (retinal degeneration 10) mouse model of retinitis pigmentosa (Zhao et al., 2015Zhao L. Zabel M.K. Wang X. Ma W. Shah P. Fariss R.N. Qian H. Parkhurst C.N. Gan W.B. Wong W.T. Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration.EMBO Mol. Med. 2015; 7: 1179-1197Crossref PubMed Scopus (261) Google Scholar, Zabel et al., 2016Zabel M.K. Zhao L. Zhang Y. Gonzalez S.R. Ma W. Wang X. Fariss R.N. Wong W.T. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa.Glia. 2016; 64: 1479-1491Crossref PubMed Scopus (119) Google Scholar). Similarly, these results diverge from those reported by Sennlaub et al., 2013Sennlaub F. Auvynet C. Calippe B. Lavalette S. Poupel L. Hu S.J. Dominguez E. Camelo S. Levy O. Guyon E. et al.CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice.EMBO Mol. Med. 2013; 5: 1775-1793Crossref PubMed Scopus (200) Google Scholar demonstrating that accumulation of mononuclear phagocytes in the subretinal space promotes chronic inflammation with IL-1β secretion that leads to severe cone-photoreceptor damage and vision loss (Eandi et al., 2016Eandi C.M. Charles Messance H. Augustin S. Dominguez E. Lavalette S. Forster V. Hu S.J. Siquieros L. Craft C.M. Sahel J.A. et al.Subretinal mononuclear phagocytes induce cone segment loss via IL-1β.eLife. 2016; 5: e16490Crossref PubMed Scopus (49) Google Scholar). These seemingly contradictory findings likely highlight a key feature of microglia and other mononuclear phagocytes: their plasticity. In other words, these cells can potentially acquire either a disease-promoting or homeostasis-maintaining phenotype depending on their tissue context, their surrounding micromilieu, and their activation state. For example, in the complex ecosystem of the neurosensory retina, it is indeed possible that the "identity" of the specific cellular and molecular signals that cause mononuclear phagocytes to migrate to the outer retina is important for specifying their activation state and thus determines whether these cells acquire a pathological or protective phenotype. The fact that the plasticity of mononuclear phagocytes determines whether they promote or prevent disease is well supported by previous work demonstrating that macrophage activation and polarization determines angiogenic fate in the retina (Kelly et al., 2007Kelly J. Ali Khan A. Yin J. Ferguson T.A. Apte R.S. Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice.J. Clin. Invest. 2007; 117: 3421-3426Crossref PubMed Scopus (179) Google Scholar, Lin et al., 2018aLin J.B. Moolani H.V. Sene A. Sidhu R. Kell P. Lin J.B. Dong Z. Ban N. Ory D.S. Apte R.S. Macrophage microRNA-150 promotes pathological angiogenesis as seen in age-related macular degeneration.JCI Insight. 2018; 3: 120157Crossref PubMed Scopus (31) Google Scholar, Lin et al., 2018bLin J.B. Sene A. Santeford A. Fujiwara H. Sidhu R. Ligon M.M. Shankar V.A. Ban N. Mysorekar I.U. Ory D.S. Apte R.S. Oxysterol Signatures Distinguish Age-Related Macular Degeneration from Physiologic Aging.EBioMedicine. 2018; 32: 9-20Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Like aged macrophages, aged microglia have also been shown to undergo programmatic changes in gene expression with age that have the potential to alter how they regulate neurodegeneration (Ma et al., 2013Ma W. Cojocaru R. Gotoh N. Gieser L. Villasmil R. Cogliati T. Swaroop A. Wong W.T. Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation.Neurobiol. Aging. 2013; 34: 2310-2321Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). It would be interesting to further examine whether the microglia niches and associated functionality reported in the present studies are perturbed during aging, as retinal microglia may be particularly vulnerable to age-associated changes, given their longevity. Another intriguing finding from the present study is that the authors noted an inability of monocyte-derived macrophages to occupy the subretinal space, even when retinal microglia were depleted. These findings are in contrast with prior work suggesting that monocyte-derived cells can indeed access the subretinal space (Sennlaub et al., 2013Sennlaub F. Auvynet C. Calippe B. Lavalette S. Poupel L. Hu S.J. Dominguez E. Camelo S. Levy O. Guyon E. et al.CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice.EMBO Mol. Med. 2013; 5: 1775-1793Crossref PubMed Scopus (200) Google Scholar, Eandi et al., 2016Eandi C.M. Charles Messance H. Augustin S. Dominguez E. Lavalette S. Forster V. Hu S.J. Siquieros L. Craft C.M. Sahel J.A. et al.Subretinal mononuclear phagocytes induce cone segment loss via IL-1β.eLife. 2016; 5: e16490Crossref PubMed Scopus (49) Google Scholar). These contrasting findings suggest that there are niches within the retina that are restricted to particular lineages of mononuclear phagocytes in certain tissue contexts and/or disease states. It would indeed be interesting to explore this issue further in other animal models and, more importantly, determine whether these niches also exist in the context of human disease. Further complicating matters is the possibility that, in various disease states, there may be disruption of the blood-retina barrier, thereby allowing non-physiologic migration of cells into niches that would otherwise be inaccessible under homeostatic conditions. Nonetheless, this present work provides important insight into the role of retinal microglia in health and disease and a strong foundation from which to investigate these remaining questions further. This work was supported by NIH grants R01 EY019287, R21 EY026707, and P30 EY002687; the Jeffrey Fort Innovation Fund; the Starr Foundation; and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology & Visual Sciences of Washington University School of Medicine. J.B.L. was supported by NIH grants T32 GM007200, UL1 TR002345, and TL1 TR002344. The authors thank Danyel Cavazos for help with scientific illustration. Microglial Function Is Distinct in Different Anatomical Locations during Retinal Homeostasis and DegenerationO'Koren et al.ImmunityMarch 5, 2019In BriefWhether microglia that reside in different central nervous system niches have distinct functions is unclear. O'Koren and Yu et al. now reveal key functional differences in microglia across two anatomically distinct locations in the retina during homeostasis. Furthermore, in degenerative conditions, microglia migrate to another location where they undergo transcriptional reprogramming and contribute to retinal cytoprotection. Full-Text PDF Open Archive