Systemic monocytes, tissue resident macrophages, dendritic cells and microglia have specific roles in immune surveillance and maintenance of tissue homeostasis and are key regulator and effector cells of the local immune response to acute and chronic tissue injury.
Two major signalling pathways that differentially define trafficking behaviour and activation of systemic and local myeloid cell populations in response to exogenous and endogenous inflammatory stimuli are the Ccl2-Ccr2 and the Cx3cl1-Cx3cr1 chemokine pathways.
Alterations in these pathways have been implicated in controlling myeloid cell activation during normal ageing and in age-related retinal degenerations, including age-related macular degeneration (AMD).
We review the evidence for how altered chemokine signalling in acute and chronic inflammatory conditions regulate local and systemic myeloid cell responses in the retina and how this may contribute to or attenuate pathology in inherited and age-related retinal diseases. We discuss the role of environmental factors (e.g. light exposure) and the influence of genetic factors on the manifestation of pathology in experimental models and in human patients and how we envisage harnessing this knowledge for the development of targeted, more broadly applicable anti-inflammatory treatment strategies for a wide range of retinal degenerations.
Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW et al (2000) Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20:4106–4114PubMedCentralPubMedCrossRefGoogle Scholar
Tacke F, Randolph GJ (2006) Migratory fate and differentiation of blood monocyte subsets. Immunobiology 211:609–618PubMedCrossRefGoogle Scholar
Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW et al (1998) Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 187:601–608PubMedCentralPubMedCrossRefGoogle Scholar
Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82PubMedCrossRefGoogle Scholar
Silverman MD, Zamora DO, Pan Y, Texeira PV, Baek SH et al (2003) Constitutive and inflammatory mediator-regulated fractalkine expression in human ocular tissues and cultured cells. Invest Ophthalmol Vis Sci 44:1608–1615PubMedCrossRefGoogle Scholar
Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K et al (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385:640–644PubMedCrossRefGoogle Scholar
Xu H, Manivannan A, Dawson R, Crane IJ, Mack M et al (2005) Differentiation to the CCR2+ inflammatory phenotype in vivo is a constitutive, time-limited property of blood monocytes and is independent of local inflammatory mediators. J Immunol 175:6915–6923PubMedCentralPubMedCrossRefGoogle Scholar
Chen M, Copland DA, Zhao J, Liu J, Forrester JV et al (2012) Persistent inflammation subverts thrombospondin-1-induced regulation of retinal angiogenesis and is driven by CCR2 Ligation. Am J Pathol 180:235–245PubMedCrossRefGoogle Scholar
Luhmann UFO, Robbie S, Munro PM, Barker SE, Duran Y et al (2009) The drusen-like phenotype in aging Ccl2 knockout mice is caused by an accelerated accumulation of swollen autofluorescent subretinal macrophages. Invest Ophthalmol Vis Sci 50:5934–5943PubMedCentralPubMedCrossRefGoogle Scholar
Nakazawa T, Hisatomi T, Nakazawa C, Noda K, Maruyama K et al (2007) From the cover: monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis. PNAS 104:2425–2430PubMedCentralPubMedCrossRefGoogle Scholar
Rutar M, Natoli R, Provis J (2012) Small interfering RNA-mediated suppression of Ccl2 in Muller cells attenuates microglial recruitment and photoreceptor death following retinal degeneration. J Neuroinflammation 9:221PubMedCentralPubMedCrossRefGoogle Scholar
Huang D, Tani M, Wang J, Han Y, He TT et al (2002) Pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractant protein-1 overexpression in mice. J Neurosci 22:10633–10642PubMedGoogle Scholar
Kezic J, McMenamin PG (2010) The monocyte chemokine receptor CX3CR1 does not play a significant role in the pathogenesis of experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 51:5121–5127PubMedCrossRefGoogle Scholar
Combadiere C, Feumi C, Raoul W, Keller N, Rodero M et al (2007) CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest 117:2920–2928PubMedCentralPubMedCrossRefGoogle Scholar
Zhang M, Xu G, Liu W, Ni Y, Zhou W (2012) Role of fractalkine/CX3CR1 interaction in light-induced photoreceptor degeneration through regulating retinal microglial activation and migration. PLoS ONE 7:e35446Google Scholar
Seidler S, Zimmermann H, Bartneck M, Trautwein C, Tacke F (2010) Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol 11:30PubMedCentralPubMedCrossRefGoogle Scholar
Grunin M, Burstyn-Cohen T, Hagbi-Levi S, Peled A, Chowers I (2012) Chemokine receptor expression in peripheral blood monocytes from patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 53:5292–5300PubMedCrossRefGoogle Scholar
Jonas JB, Tao Y, Neumaier M, Findeisen P (2012) Cytokine concentration in aqueous humour of eyes with exudative age-related macular degeneration. Acta Ophthalmol 90(5):e381–388CrossRefGoogle Scholar
Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC et al (2003) An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med 9:1390–1397PubMedCrossRefGoogle Scholar
Chen M, Forrester JV, Xu H (2011) Dysregulation in retinal para-inflammation and age-related retinal degeneration in CCL2 or CCR2 deficient mice. PLoS ONE 6:e22818Google Scholar
Luhmann UFO, Carvalho LS, Robbie SJ, Cowing JA, Duran Y et al (2013) Ccl2, Cx3cr1 and Ccl2/Cx3cr1 chemokine deficiencies are not sufficient to cause age-related retinal degeneration. Exp Eye Res 107:80–87PubMedCentralPubMedCrossRefGoogle Scholar
Chinnery HR, McLenachan S, Humphries T, Kezic JM, Chen X et al (2012) Accumulation of murine subretinal macrophages: effects of age, pigmentation and CX3CR1. Neurobiol Aging 33(8):1769–1776PubMedCrossRefGoogle Scholar
Luhmann UFO, Lange CA, Robbie S, Munro PMG, Cowing JA et al (2012) Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling. PLoS ONE 7:e35551CrossRefGoogle Scholar
Ng TF, Streilein JW (2001) Light-induced migration of retinal microglia into the subretinal space. Invest Ophthalmol Vis Sci 42:3301–3310PubMedGoogle Scholar