Reduced photoreceptor death and improved retinal function during retinal degeneration in mice lacking innate immunity adaptor protein MyD88.
The injury inflammatory response mediated by the innate immune system is an important contributor to neurodegeneration in the central nervous system (CNS) and retina. A major branch of the innate immune system is regulated by the Toll-like receptors (TLRs), which are receptors for endogenous damage associated molecules released from injured cells as well as pathogen-derived molecules, and interleukin-1 receptors (IL-1R), which are activated by IL-1α, IL-1β and IL-18 cytokines. TLRs and IL-1R are expressed on immune and non-immune cell types and act as first responders to cell damage, which results in tissue repair, or inflammation and apoptosis. Both TLR and IL-1R require the adaptor protein myeloid differentiation primary response gene 88 (MyD88) for signaling. Although inflammation is implicated in neuronal death in the retina, the role of MyD88-dependent TLR and IL-1R signaling in retinal degeneration is unknown. Therefore, the purpose of this study was to investigate the role of MyD88-mediated signaling in neuronal degeneration in the retinal degeneration 1 (rd1) mouse model, which exhibits a phenotype of rapid photoreceptor death and inflammation. To generate rd1 mice lacking the MyD88 gene, rd1 were bred with MyD88 knockout mice (MyD88(-/-)) for several generations to produce rd1/MyD88(+/+) and rd1/MyD88(-/-) genotypes. Chemokine mRNA expression levels were analyzed by qRT-PCR, and recruitment of activated microglia was quantified by immunodetection of the IBA-1 protein. Retinal outer nuclear layer cell counts were performed to quantify photoreceptor degeneration, and retinal function was assessed using electroretinograms (ERG). Our results revealed that retinal expression of Ccl2, Ccl4, Ccl7 and Cxcl10 was reduced by 2 to 8-fold in rd1/MyD88(-/-) mice compared with rd1/MyD88(+/+) mice (p<0.05), which coincided with attenuated microglial activation, higher numbers of photoreceptors and higher retina responses to photopic and scotopic stimuli. At later ages, rd1/MyD88(-/-) had reduced chemokine expression and higher photopic responses but no change in microglial recruitment compared with rd1 mice with functional MyD88. In conclusion, lack of MyD88-mediated signaling increased photoreceptor survival and retina function in rd1 mice, which implicates MyD88-mediated innate immunity pathways as an important pathogenic factor during retinal degeneration.
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, McKnight Bldg., Rm. 407, 1638 NW 10th Ave., Miami, FL 33136, USA.
Sarah
S
Syeda
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, McKnight Bldg., Rm. 407, 1638 NW 10th Ave., Miami, FL 33136, USA.
Amit K
AK
Patel
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, McKnight Bldg., Rm. 407, 1638 NW 10th Ave., Miami, FL 33136, USA.
Tinthu
T
Lee
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, McKnight Bldg., Rm. 407, 1638 NW 10th Ave., Miami, FL 33136, USA. Electronic address: ahackam@med.miami.edu.
Abigail S
AS
Hackam
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics; D004195:Disease Models, Animal; D004596:Electroretinography; D005786:Gene Expression Regulation / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction / Q000235:genetics
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D018925:Chemokines; D008840:Microfilament Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse
Chemokines; IL-1R; Innate immunity; Microglia; MyD88; Photoreceptor; Retina; Retinal degeneration; TLR signaling