Key Points
-
Pathological lymphangiogenesis of the adult cornea is associated with breach of corneal immune privilege and can allow cells of the mononuclear phagocyte system (MPS) to trigger T cell responses.
-
Severing corneal nerves in one eye causes a breach in corneal immune privilege in both eyes, suggesting the presence of a neuro-immune reflex that may involve MPS cells.
-
Commensals in the gut, and perhaps gut MPS cells, are capable of triggering T cells that cause autoimmune responses in the immune privileged retina.
-
Microglia have a key role in shaping healthy synapses in the visual system, but these cells may also contribute to retinal ganglion cell dysfunction in glaucoma.
-
Microglia and monocyte-derived cells are both present in the retina in a model of photoreceptor degeneration and these distinct MPS lineages have phenotypic differences, as confirmed in CX3CR1Cre reporter systems.
-
Early studies using such CX3CR1Cre systems suggest that functional specializations of microglia versus monocyte-derived cells accounts for their distinct roles in photoreceptor degenerative diseases.
Abstract
Major advances in mononuclear phagocyte biology have been made but key questions pertinent to their roles in health and disease remain, including in the visual system. One problem concerns how dendritic cells can trigger immune responses from certain tightly regulated immune- privileged sites of the eye. Another, albeit separate, problem involves whether there are functional specializations for microglia versus monocytes in retinal neurodegeneration. In this Review, we examine novel insights in eye immune privilege and, separately, we discuss recent inroads concerning retinal degeneration. Both themes have been extensively studied in the visual system and show parallels with recent findings concerning mononuclear phagocytes in the central nervous system and in the periphery.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ginhoux, F., Guilliams, M. & Naik, S. H. Editorial: dendritic cell and macrophage nomenclature and classification. Front. Immunol. 7, 168 (2016).
Guilliams, M. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14, 571–578 (2014).
Geissmann, F., Gordon, S., Hume, D. A., Mowat, A. M. & Randolph, G. J. Unravelling mononuclear phagocyte heterogeneity. Nat. Rev. Immunol. 10, 453–460 (2010).
Mildner, A., Yona, S. & Jung, S. A close encounter of the third kind: monocyte-derived cells. Adv. Immunol. 120, 69–103 (2013).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This study shows that yolk sac macrophages in utero give rise to microglia in the adult setting.
Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
Hoeffel, G. et al. C-MYB+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).
Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via PU.1- and IRF8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).
Shemer, A. & Jung, S. Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity. Semin. Immunopathol. 37, 613–623 (2015).
Ginhoux, F. & Prinz, M. Origin of microglia: current concepts and past controversies. Cold Spring Harb. Perspect. Biol. 7, a020537 (2015).
Streilein, J. W. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat. Rev. Immunol. 3, 879–889 (2003). This review covers tolerogenic immune networks that have a central role in ocular immune privilege and anterior-associated immune deviation.
Ridge, J. P., Fuchs, E. J. & Matzinger, P. Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science 271, 1723–1726 (1996).
Fijak, M. & Meinhardt, A. The testis in immune privilege. Immunol. Rev. 213, 66–81 (2006).
Forrester, J. V., Xu, H., Lambe, T. & Cornall, R. Immune privilege or privileged immunity? Mucosal Immunol. 1, 372–381 (2008). This review covers our recent understanding of immune privilege and the different mechanisms that support this setting in various organ systems.
Galea, I., Bechmann, I. & Perry, V. H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007).
Mellor, A. L. & Munn, D. H. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat. Rev. Immunol. 8, 74–80 (2008).
Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).
Niederkorn, J. Y. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat. Immunol. 7, 354–359 (2006).
Combadiere, C. et al. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J. Clin. Invest. 117, 2920–2928 (2007).
Mo, J. S. et al. By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA/2J pigmentary glaucoma. J. Exp. Med. 197, 1335–1344 (2003).
Benhar, I., London, A. & Schwartz, M. The privileged immunity of immune privileged organs: the case of the eye. Front. Immunol. 3, 296 (2012).
Housset, M. & Sennlaub, F. Thrombospondin-1 and pathogenesis of age-related macular degeneration. J. Ocul. Pharmacol. Ther. 31, 406–412 (2015).
Perez, V. L. & Caspi, R. R. Immune mechanisms in inflammatory and degenerative eye disease. Trends Immunol. 36, 354–363 (2015).
Zamiri, P., Sugita, S. & Streilein, J. W. Immunosuppressive properties of the pigmented epithelial cells and the subretinal space. Chem. Immunol. Allergy 92, 86–93 (2007).
Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).
Schulz, C. et al. A lineage of myeloid cells independent of MYB and hematopoietic stem cells. Science 336, 86–90 (2012).
Caspi, R. R. Ocular autoimmunity: the price of privilege? Immunol. Rev. 213, 23–35 (2006).
Saban, D. R. The chemokine receptor CCR7 expressed by dendritic cells: a key player in corneal and ocular surface inflammation. Ocul. Surf. 12, 87–99 (2014).
Forrester, J. V., Xu, H., Kuffova, L., Dick, A. D. & McMenamin, P. G. Dendritic cell physiology and function in the eye. Immunol. Rev. 234, 282–304 (2010).
Lucas, K., Karamichos, D., Mathew, R., Zieske, J. D. & Stein-Streilein, J. Retinal laser burn-induced neuropathy leads to substance P-dependent loss of ocular immune privilege. J. Immunol. 189, 1237–1242 (2012).
Tilney, N. L. Patterns of lymphatic drainage in the adult laboratory rat. J. Anat. 109, 369–383 (1971).
Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).
Louveau, A. et al. Corrigendum: structural and functional features of central nervous system lymphatic vessels. Nature 533, 278 (2016).
Camelo, S., Kezic, J., Shanley, A., Rigby, P. & McMenamin, P. G. Antigen from the anterior chamber of the eye travels in a soluble form to secondary lymphoid organs via lymphatic and vascular routes. Invest. Ophthalmol. Vis. Sci. 47, 1039–1046 (2006).
Erlebacher, A., Vencato, D., Price, K. A., Zhang, D. & Glimcher, L. H. Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J. Clin. Invest. 117, 1399–1411 (2007).
Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
Collin, H. B. Lymphatic drainage of 131-I-albumin from the vascularized cornea. Invest. Ophthalmol. 9, 146–155 (1970). This original study characterizes the kinetics of antigen drainage to the lymphatics from the pauci-lymphatic cornea.
Billingham, R. E. & Boswell, T. Studies on the problem of corneal homografts. Proc. R. Soc. Lond. B 141, 392–406 (1953).
Chang, J. H., Gabison, E. E., Kato, T. & Azar, D. T. Corneal neovascularization. Curr. Opin. Ophthalmol. 12, 242–249 (2001).
Wong, H. L. et al. MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis. Nat. Commun. 7, 10824 (2016).
Cursiefen, C. et al. Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J. Exp. Med. 208, 1083–1092 (2011).
Seo, S. et al. Forkhead box transcription factor FOXC1 preserves corneal transparency by regulating vascular growth. Proc. Natl Acad. Sci. USA 109, 2015–2020 (2012).
Albuquerque, R. J. et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat. Med. 15, 1023–1030 (2009).
Singh, N. et al. Soluble vascular endothelial growth factor receptor 3 is essential for corneal alymphaticity. Blood 121, 4242–4249 (2013).
Lee, H. S. et al. Involvement of corneal lymphangiogenesis in a mouse model of allergic eye disease. Invest. Ophthalmol. Vis. Sci. 56, 3140–3148 (2015).
Ahadome, S. D. et al. Classical dendritic cells mediate fibrosis directly via the retinoic acid pathway in severe eye allergy. JCI Insight 1, e87012 (2016).
Cursiefen, C. et al. Lymphatic vessels in vascularized human corneas: immunohistochemical investigation using LYVE-1 and podoplanin. Invest. Ophthalmol. Vis. Sci. 43, 2127–2135 (2002).
Wuest, T. R. & Carr, D. J. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J. Exp. Med. 207, 101–115 (2010).
Chauhan, S. K. et al. A novel pro-lymphangiogenic function for TH17/IL-17. Blood 118, 4630–4634 (2011).
Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).
Cursiefen, C. et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J. Clin. Invest. 113, 1040–1050 (2004).
Chen, W. S. et al. Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3. Nat. Commun. 7, 11302 (2016).
Bock, F. et al. Novel anti(lymph)angiogenic treatment strategies for corneal and ocular surface diseases. Prog. Retin. Eye Res. 34, 89–124 (2013).
Maruyama, K. et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J. Clin. Invest. 115, 2363–2372 (2005).
Chen, L. et al. Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nat. Med. 10, 813–815 (2004). This study shows that antigen-presenting cells from the cornea migrate to the draining lymph node.
Hamrah, P., Liu, Y., Zhang, Q. & Dana, M. R. Alterations in corneal stromal dendritic cell phenotype and distribution in inflammation. Arch. Ophthalmol. 121, 1132–1140 (2003).
Saban, D. R., Bock, F., Chauhan, S. K., Masli, S. & Dana, R. Thrombospondin-1 derived from APCs regulates their capacity for allosensitization. J. Immunol. 185, 4691–4697 (2010).
Pajoohesh-Ganji, A. et al. Partial denervation of sub-basal axons persists following debridement wounds to the mouse cornea. Lab. Invest. 95, 1305–1318 (2015).
Dietrich, T. et al. Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J. Immunol. 184, 535–539 (2010).
Dana, M. R. & Streilein, J. W. Loss and restoration of immune privilege in eyes with corneal neovascularization. Invest. Ophthalmol. Vis. Sci. 37, 2485–2494 (1996).
Chen, Y., Chauhan, S. K., Lee, H. S., Saban, D. R. & Dana, R. Chronic dry eye disease is principally mediated by effector memory TH17 cells. Mucosal Immunol. 7, 38–45 (2014).
Gandhi, N. B. et al. Dendritic cell-derived thrombospondin-1 is critical for the generation of the ocular surface TH17 response to desiccating stress. J. Leukoc. Biol. 94, 1293–1301 (2013).
Zhang, X. et al. CD8+ cells regulate the T helper 17 response in an experimental murine model of Sjogren syndrome. Mucosal Immunol. 7, 417–427 (2014).
Schlereth, S., Lee, H. S., Khandelwal, P. & Saban, D. R. Blocking CCR7 at the ocular surface impairs the pathogenic contribution of dendritic cells in allergic conjunctivitis. Am. J. Pathol. 180, 2351–2360 (2012).
Hos, D. et al. Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation. Exp. Res. 146, 1–6 (2016).
Hua, J. et al. Graft site microenvironment determines dendritic cell trafficking through the CCR7–CCL19/21 axis. Invest. Ophthalmol. Vis. Sci. 57, 1457–1467 (2016).
Kodati, S. et al. CCR7 is critical for the induction and maintenance of TH17 immunity in dry eye disease. Invest. Ophthalmol. Vis. Sci. 55, 5871–5877 (2014).
Dang, Z., Kuffova, L., Liu, L. & Forrester, J. V. Soluble antigen traffics rapidly and selectively from the corneal surface to the eye draining lymph node and activates T cells when codelivered with CpG oligonucleotides. J. Leukoc. Biol. 95, 431–440 (2014).
Taylor, A. W., Streilein, J. W. & Cousins, S. W. Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor. J. Immunol. 153, 1080–1086 (1994).
Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).
Gabanyi, I. et al. Neuro–immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).
Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013).
Paunicka, K. J. et al. Severing corneal nerves in one eye induces sympathetic loss of immune privilege and promotes rejection of future corneal allografts placed in either eye. Am. J. Transplant. 15, 1490–1501 (2015). This study shows that severing corneal nerves in a certain manner in one eye leads to a bilateral breach in corneal immune privilege.
Niederkorn, J. Y. Cornea: window to ocular immunology. Curr. Immunol. Rev. 7, 328–335 (2011).
Niederkorn, J. Y. & Larkin, D. F. Immune privilege of corneal allografts. Ocul. Immunol. Inflamm. 18, 162–171 (2010).
Lucas, L., Karamichos, D., Mathew, R., Zieske, J. D. & Stein-Streilein, J. Retinal laser burn-induced neuropathy leads to substance P-dependent loss of ocular immune privilege. J. Immunol. 189, 1237–1242 (2009).
Forrester, J. V. & Xu, H. Good news-bad news: the Yin and Yang of immune privilege in the eye. Front. Immunol. 3, 338 (2012).
Pavlov, V. A. & Tracey, K. J. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat. Neurosci. 20, 156–166 (2017).
Blanco, T. & Saban, D. R. The cornea has “the nerve” to encourage immune rejection. Am. J. Transplant. 15, 1453–1454 (2015). This review covers the neuro-immune reflex responses in health and disease.
Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).
Kashem, S. W. et al. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43, 515–526 (2015).
Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014).
Gao, N., Yan, C., Lee, P., Sun, H. & Yu, F. S. Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea. J. Clin. Invest. 126, 1998–2011 (2016).
Seyed-Razavi, Y., Chinnery, H. R. & McMenamin, P. G. A novel association between resident tissue macrophages and nerves in the peripheral stroma of the murine cornea. Invest. Ophthalmol. Vis. Sci. 55, 1313–1320 (2014).
Clarke, D. W. & Niederkorn, J. Y. The pathophysiology of Acanthamoeba keratitis. Trends Parasitol. 22, 175–180 (2006).
Cruzat, A. et al. Contralateral clinically unaffected eyes of patients with unilateral infectious keratitis demonstrate a sympathetic immune response. Invest. Ophthalmol. Vis. Sci. 56, 6612–6620 (2015).
Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).
Kugadas, A. & Gadjeva, M. Impact of microbiome on ocular health. Ocul. Surf. 14, 342–349 (2016).
Evaldson, G., Heimdahl, A., Kager, L. & Nord, C. E. The normal human anaerobic microflora. Scand. J. Infect. Dis. Suppl. 35, 9–15 (1982).
Larkin, D. F. & Leeming, J. P. Quantitative alterations of the commensal eye bacteria in contact lens wear. Eye (Lond.) 5, 70–74 (1991).
Horai, R. et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity 43, 343–353 (2015). This study shows that gut commensals result in T cell autoreactivity that cause experimental autoimmune uveitis.
Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).
Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4615–4622 (2011).
Moser, B. & Brandes, M. Gammadelta T cells: an alternative type of professional APC. Trends Immunol. 27, 112–118 (2006).
Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).
Erny, D., Hrabe de Angelis, A. L. & Prinz, M. Communicating systems in the body: how microbiota and microglia cooperate. Immunology 150, 7–15 (2017).
Biber, K., Moller, T., Boddeke, E. & Prinz, M. Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat. Rev. Drug Discov. 15, 110–124 (2016).
Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).
Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).
Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009).
Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).
Tremblay, M. E., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).
Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007). This study shows the role of C1q in synaptic pruning in development and axonal neurodegeneration in the visual system of DBA/2J mice.
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012). This study shows the role of microglia in C1q-mediated pruning of synapses.
Anderson, M. G. et al. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat. Genet. 30, 81–85 (2002).
Howell, G. R. et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J. Clin. Invest. 121, 1429–1444 (2011).
Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). This study shows that microglia-mediated elimination of synapses is involved in the pathogenesis of Alzheimer disease in mouse models.
Vasek, M. J. et al. A complement–microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016).
Hageman, G. S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl Acad. Sci. USA 102, 7227–7232 (2005).
Toomey, C. B., Kelly, U., Saban, D. R. & Bowes Rickman, C. Regulation of age-related macular degeneration-like pathology by complement factor H. Proc. Natl Acad. Sci. USA 112, E3040–E3049 (2015).
Ding, J. D. et al. The role of complement dysregulation in AMD mouse models. Adv. Exp. Med. Biol. 801, 213–219 (2014).
London, A. et al. Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J. Exp. Med. 208, 23–39 (2011).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012).
Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).
Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).
Caicedo, A., Espinosa-Heidmann, D. G., Pina, Y., Hernandez, E. P. & Cousins, S. W. Blood-derived macrophages infiltrate the retina and activate Muller glial cells under experimental choroidal neovascularization. Exp. Res. 81, 38–47 (2005).
O'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. 6, 20636 (2016). This study shows that microglia and monocyte-derived macrophages are both present in a retinal degeneration model and are characterized their phenotypic differences.
Sennlaub, F. 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. 5, 1775–1793 (2013).
Xu, H., Chen, M., Mayer, E. J., Forrester, J. V. & Dick, A. D. Turnover of resident retinal microglia in the normal adult mouse. Glia 55, 1189–1198 (2007).
Mildner, A. et al. Microglia in the adult brain arise from LY6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 1544–1553 (2007).
Sedgwick, J. D. et al. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc. Natl Acad. Sci. USA 88, 7438–7442 (1991).
Dick, A. D., Ford, A. L., Forrester, J. V. & Sedgwick, J. D. Flow cytometric identification of a minority population of MHC class II-positive cells in the normal rat retina distinct from CD45lowCD11b/c+CD4low parenchymal microglia. Br. J. Ophthalmol. 79, 834–840 (1995).
Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014).
Luckoff, A. et al. Interferon-β signaling in retinal mononuclear phagocytes attenuates pathological neovascularization. EMBO Mol. Med. 8, 670–678 (2016).
Pharmacological Therapy for Macular Degeneration Study Group. Interferon-α2a is ineffective for patients with choroidal neovascularization secondary to age-related macular degeneration. Results of a prospective randomized placebo-controlled clinical trial. Arch. Ophthalmol. 115, 865–872 (1997).
Zhao, L. et al. Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Mol. Med. 7, 1179–1197 (2015).
Guo, C. et al. Knockout of CCR2 alleviates photoreceptor cell death in a model of retinitis pigmentosa. Exp. Res. 104, 39–47 (2012).
Eandi, C. M. et al. Subretinal mononuclear phagocytes induce cone segment loss via IL-1β. eLife 5, e16490 (2016).
Xi, H. et al. IL-33 amplifies an innate immune response in the degenerating retina. J. Exp. Med. 213, 189–207 (2016).
Theodoropoulou, S. et al. Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye. J. Pathol. 241, 45–56 (2017).
Gadani, S. P., Walsh, J. T., Smirnov, I., Zheng, J. & Kipnis, J. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron 85, 703–709 (2015).
Amit, I., Winter, D. R. & Jung, S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 17, 18–25 (2016).
Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).
van de Laar, L. et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity 44, 755–768 (2016).
Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).
Medawar, P. B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29, 58–69 (1948).
Kaur, G., Mital, P. & Dufour, J. M. Testisimmune privilege — assumptions versus facts. Anim. Reprod. 10, 3–15 (2013).
Streilein, J. W. & Niederkorn, J. Y. Induction of anterior chamber-associated immune deviation requires an intact, functional spleen. J. Exp. Med. 153, 1058–1067 (1981).
Lin, H. H. et al. The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance. J. Exp. Med. 201, 1615–1625 (2005).
Streilein, J. W. & Stein-Streilein, J. Does innate immune privilege exist? J. Leukoc. Biol. 67, 479–487 (2000).
Acknowledgements
The authors are supported by grants from the US National Institutes of Health (R01 to D.R.S. and F32 to N.J.R.) and Research to Prevent Blindness (to D.R.S.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Reyes, N., O'Koren, E. & Saban, D. New insights into mononuclear phagocyte biology from the visual system. Nat Rev Immunol 17, 322–332 (2017). https://doi.org/10.1038/nri.2017.13
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri.2017.13
- Springer Nature Limited
This article is cited by
-
Macrophage activation contributes to diabetic retinopathy
Journal of Molecular Medicine (2024)
-
HIF1α-dependent hypoxia response in myeloid cells requires IRE1α
Journal of Neuroinflammation (2023)
-
Shedding light on macrophage immunotherapy in lung cancer
Journal of Cancer Research and Clinical Oncology (2023)
-
The innate immune receptor Nlrp12 suppresses autoimmunity to the retina
Journal of Neuroinflammation (2022)
-
Cellular components of the idiopathic epiretinal membrane
Graefe's Archive for Clinical and Experimental Ophthalmology (2022)