{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:46:40Z","timestamp":1790470000668,"version":"4.1.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,9,7]],"date-time":"2020-09-07T00:00:00Z","timestamp":1599436800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,9,7]],"date-time":"2020-09-07T00:00:00Z","timestamp":1599436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"This work was supported by the RIKEN Junior Research Associate Program. In addition, this study was also supported by grants from KAKENHI","award":["25293357"],"award-info":[{"award-number":["25293357"]}]},{"name":"This work was supported by the RIKEN Junior Research Associate Program. In addition, this study was also supported by grants from KAKENHI","award":["18H02959"],"award-info":[{"award-number":["18H02959"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression. To understand the origin and the diagnostic interpretation of the fundus color and FAF, we performed in vivo imaging of fundus color and FAF together with histological analyses of the retinal degeneration process using the RP model mice, <jats:italic>rd10<\/jats:italic>. FAF partly represented the accumulation of microglia in the photoreceptor outer segments. Fundus whitening suggested the presence of apoptotic cells, which spatiotemporally preceded increase in FAF. We observed two patterns of FAF localization, arcuate and diffuse, each indicating different pattern of apoptosis, wavy and diffuse, respectively. Diffuse pattern of apoptosis was suppressed in dark-raised <jats:italic>rd10<\/jats:italic> mice, in which outer nuclear layer (ONL) loss was significantly suppressed. The occupancy of FAF correlated with the thinning rate of the ONL. Fractalkine, a microglia chemotactic factor, was detected in apoptotic photoreceptors, suggesting chemokine-induced recruitment of microglia into the ONL, which paralleled with accelerated ONL loss and increased FAF occupancy. Thus, we propose that the degree of photoreceptor apoptosis and the rate of ONL thinning in RP patients might be read from the fundus color and the FAF.<\/jats:p>","DOI":"10.1038\/s41598-020-71626-2","type":"journal-article","created":{"date-parts":[[2020,9,7]],"date-time":"2020-09-07T10:02:52Z","timestamp":1599472972000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Microglia dynamics in retinitis pigmentosa model: formation of fundus whitening and autofluorescence as an indicator of activity of retinal degeneration"],"prefix":"10.1038","volume":"10","author":[{"given":"Kenichi","family":"Makabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunao","family":"Sugita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Mandai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Futatsugi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayo","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,7]]},"reference":[{"key":"71626_CR1","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1016\/S0140-6736(06)69740-7","volume":"368","author":"DT Hartong","year":"2006","unstructured":"Hartong, D. T., Berson, E. L. & Dryja, T. P. Retinitis pigmentosa. Lancet 368, 1795\u20131809. https:\/\/doi.org\/10.1016\/S0140-6736(06)69740-7 (2006).","journal-title":"Lancet"},{"key":"71626_CR2","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.ajo.2007.11.018","volume":"145","author":"T Murakami","year":"2008","unstructured":"Murakami, T. et al. Association between abnormal autofluorescence and photoreceptor disorganization in retinitis pigmentosa. Am. J. Ophthalmol. 145, 687\u2013694. https:\/\/doi.org\/10.1016\/j.ajo.2007.11.018 (2008).","journal-title":"Am. J. Ophthalmol."},{"key":"71626_CR3","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1016\/j.ajo.2011.08.043","volume":"153","author":"LH Lima","year":"2012","unstructured":"Lima, L. H. et al. Progressive constriction of the hyperautofluorescent ring in retinitis pigmentosa. Am. J. Ophthalmol. 153, 718\u2013727. https:\/\/doi.org\/10.1016\/j.ajo.2011.08.043 (2012).","journal-title":"Am. J. Ophthalmol."},{"key":"71626_CR4","doi-asserted-by":"publisher","first-page":"3544","DOI":"10.1167\/iovs.02-1278","volume":"44","author":"AG Robson","year":"2003","unstructured":"Robson, A. G. et al. Pattern ERG correlates of abnormal fundus autofluorescence in patients with retinitis pigmentosa and normal visual acuity. Invest. Ophthalmol. Vis. Sci. 44, 3544\u20133550 (2003).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"71626_CR5","doi-asserted-by":"publisher","first-page":"15326","DOI":"10.1074\/jbc.M112.448712","volume":"288","author":"H Kohno","year":"2013","unstructured":"Kohno, H. et al. Photoreceptor proteins initiate microglial activation via Toll-like receptor 4 in retinal degeneration mediated by all-trans-retinal. J. Biol. Chem. 288, 15326\u201315341. https:\/\/doi.org\/10.1074\/jbc.M112.448712 (2013).","journal-title":"J. Biol. Chem."},{"key":"71626_CR6","doi-asserted-by":"publisher","first-page":"8534","DOI":"10.1167\/iovs.11-8012","volume":"52","author":"T Sekiryu","year":"2011","unstructured":"Sekiryu, T., Oguchi, Y., Arai, S., Wada, I. & Iida, T. Autofluorescence of the cells in human subretinal fluid. Invest. Ophthalmol. Vis. Sci. 52, 8534\u20138541. https:\/\/doi.org\/10.1167\/iovs.11-8012 (2011).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"71626_CR7","doi-asserted-by":"publisher","first-page":"6031","DOI":"10.1167\/iovs.14-15091","volume":"55","author":"SY Kim","year":"2014","unstructured":"Kim, S. Y. et al. Deletion of aryl hydrocarbon receptor AHR in mice leads to subretinal accumulation of microglia and RPE atrophy. Invest. Ophthalmol. Vis. Sci. 55, 6031\u20136040. https:\/\/doi.org\/10.1167\/iovs.14-15091 (2014).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"71626_CR8","first-page":"196","volume":"37","author":"RS Roque","year":"1996","unstructured":"Roque, R. S., Imperial, C. J. & Caldwell, R. B. Microglial cells invade the outer retina as photoreceptors degenerate in Royal College of Surgeons rats. Invest. Ophthalmol. Vis. Sci. 37, 196\u2013203 (1996).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"71626_CR9","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/S0014-4835(02)00332-9","volume":"76","author":"N Gupta","year":"2003","unstructured":"Gupta, N., Brown, K. E. & Milam, A. H. Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp. Eye Res. 76, 463\u2013471 (2003).","journal-title":"Exp. Eye Res."},{"key":"71626_CR10","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.15252\/emmm.201505298","volume":"7","author":"L Zhao","year":"2015","unstructured":"Zhao, L. et al. Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Mol. Med. 7, 1179\u20131197. https:\/\/doi.org\/10.15252\/emmm.201505298 (2015).","journal-title":"EMBO Mol. Med."},{"key":"71626_CR11","doi-asserted-by":"publisher","first-page":"e35446","DOI":"10.1371\/journal.pone.0035446","volume":"7","author":"M Zhang","year":"2012","unstructured":"Zhang, M., Xu, G., Liu, W., Ni, Y. & Zhou, W. Role of fractalkine\/CX3CR1 interaction in light-induced photoreceptor degeneration through regulating retinal microglial activation and migration. PLoS ONE 7, e35446. https:\/\/doi.org\/10.1371\/journal.pone.0035446 (2012).","journal-title":"PLoS ONE"},{"key":"71626_CR12","first-page":"765","volume":"23","author":"C Feng","year":"2017","unstructured":"Feng, C. et al. Expression of CCL2 and its receptor in activation and migration of microglia and monocytes induced by photoreceptor apoptosis. Mol. Vis. 23, 765\u2013777 (2017).","journal-title":"Mol. Vis."},{"key":"71626_CR13","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.visres.2006.11.020","volume":"47","author":"B Chang","year":"2007","unstructured":"Chang, B. et al. Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene. Vis. Res. 47, 624\u2013633. https:\/\/doi.org\/10.1016\/j.visres.2006.11.020 (2007).","journal-title":"Vis. Res."},{"key":"71626_CR14","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1097\/00006982-199212010-00006","volume":"12","author":"AM Mansour","year":"1992","unstructured":"Mansour, A. M., Green, W. R. & Hogge, C. Histopathology of commotio retinae. Retina 12, 24\u201328 (1992).","journal-title":"Retina"},{"key":"71626_CR15","first-page":"718","volume":"36","author":"FC Delori","year":"1995","unstructured":"Delori, F. C. et al. In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest. Ophthalmol. Vis. Sci. 36, 718\u2013729 (1995).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"71626_CR16","doi-asserted-by":"publisher","first-page":"4351","DOI":"10.1167\/iovs.10-5852","volume":"51","author":"JR Sparrow","year":"2010","unstructured":"Sparrow, J. R., Yoon, K. D., Wu, Y. & Yamamoto, K. Interpretations of fundus autofluorescence from studies of the bisretinoids of the retina. Invest. Ophthalmol. Vis. Sci. 51, 4351\u20134357. https:\/\/doi.org\/10.1167\/iovs.10-5852 (2010).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"71626_CR17","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jneumeth.2013.02.012","volume":"215","author":"M Molcanyi","year":"2013","unstructured":"Molcanyi, M. et al. Pitfalls and fallacies interfering with correct identification of embryonic stem cells implanted into the brain after experimental traumatic injury. J. Neurosci. Methods 215, 60\u201370. https:\/\/doi.org\/10.1016\/j.jneumeth.2013.02.012 (2013).","journal-title":"J. Neurosci. Methods"},{"key":"71626_CR18","doi-asserted-by":"publisher","first-page":"859084","DOI":"10.1155\/2015\/859084","volume":"2015","author":"O Uckermann","year":"2015","unstructured":"Uckermann, O. et al. Endogenous two-photon excited fluorescence provides label-free visualization of the inflammatory response in the rodent spinal cord. Biomed. Res. Int. 2015, 859084. https:\/\/doi.org\/10.1155\/2015\/859084 (2015).","journal-title":"Biomed. Res. Int."},{"key":"71626_CR19","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1017\/S1431927610000322","volume":"16","author":"RW Davis","year":"2010","unstructured":"Davis, R. W. et al. Accurate detection of low levels of fluorescence emission in autofluorescent background: francisella-infected macrophage cells. Microsc. Microanal. 16, 478\u2013487. https:\/\/doi.org\/10.1017\/S1431927610000322 (2010).","journal-title":"Microsc. Microanal."},{"key":"71626_CR20","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.neures.2009.08.001","volume":"65","author":"K Kosaka","year":"2009","unstructured":"Kosaka, K. et al. Distinct domanial and lamellar distribution of clustered lipofuscin granules in microglia in the main olfactory bulb of young mice. Neurosci. Res. 65, 286\u2013295. https:\/\/doi.org\/10.1016\/j.neures.2009.08.001 (2009).","journal-title":"Neurosci. Res."},{"key":"71626_CR21","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/347677a0","volume":"347","author":"C Bowes","year":"1990","unstructured":"Bowes, C. et al. Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature 347, 677\u2013680. https:\/\/doi.org\/10.1038\/347677a0 (1990).","journal-title":"Nature"},{"key":"71626_CR22","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1111\/j.1749-6632.1999.tb07837.x","volume":"893","author":"DA Fox","year":"1999","unstructured":"Fox, D. A., Poblenz, A. T. & He, L. Calcium overload triggers rod photoreceptor apoptotic cell death in chemical-induced and inherited retinal degenerations. Ann. N. Y. Acad. Sci. 893, 282\u2013285. https:\/\/doi.org\/10.1111\/j.1749-6632.1999.tb07837.x (1999).","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"71626_CR23","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1016\/j.ajo.2015.06.032","volume":"160","author":"T Sujirakul","year":"2015","unstructured":"Sujirakul, T. et al. Multimodal imaging of central retinal disease progression in a 2-year mean follow-up of retinitis pigmentosa. Am. J. Ophthalmol. 160, 786\u2013798. https:\/\/doi.org\/10.1016\/j.ajo.2015.06.032 (2015).","journal-title":"Am. J. Ophthalmol."},{"key":"71626_CR24","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1093\/brain\/awt210","volume":"136","author":"E Zotova","year":"2013","unstructured":"Zotova, E. et al. Inflammatory components in human Alzheimer\u2019s disease and after active amyloid-beta42 immunization. Brain 136, 2677\u20132696. https:\/\/doi.org\/10.1093\/brain\/awt210 (2013).","journal-title":"Brain"},{"key":"71626_CR25","doi-asserted-by":"publisher","first-page":"10896","DOI":"10.1073\/pnas.95.18.10896","volume":"95","author":"JK Harrison","year":"1998","unstructured":"Harrison, J. K. et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. USA 95, 10896\u201310901 (1998).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"71626_CR26","doi-asserted-by":"publisher","first-page":"e106562","DOI":"10.1371\/journal.pone.0106562","volume":"9","author":"M Zieger","year":"2014","unstructured":"Zieger, M., Ahnelt, P. K. & Uhrin, P. CX3CL1 (fractalkine) protein expression in normal and degenerating mouse retina: in vivo studies. PLoS ONE 9, e106562. https:\/\/doi.org\/10.1371\/journal.pone.0106562 (2014).","journal-title":"PLoS ONE"},{"key":"71626_CR27","doi-asserted-by":"publisher","first-page":"360","DOI":"10.3389\/fncel.2014.00360","volume":"8","author":"JD Sokolowski","year":"2014","unstructured":"Sokolowski, J. D., Chabanon-Hicks, C. N., Han, C. Z., Heffron, D. S. & Mandell, J. W. Fractalkine is a \u201cfind-me\u201d signal released by neurons undergoing ethanol-induced apoptosis. Front. Cell. Neurosci. 8, 360. https:\/\/doi.org\/10.3389\/fncel.2014.00360 (2014).","journal-title":"Front. Cell. Neurosci."},{"key":"71626_CR28","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1002\/glia.23016","volume":"64","author":"MK Zabel","year":"2016","unstructured":"Zabel, M. K. et al. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa. Glia 64, 1479\u20131491. https:\/\/doi.org\/10.1002\/glia.23016 (2016).","journal-title":"Glia"},{"key":"71626_CR29","doi-asserted-by":"publisher","first-page":"12803","DOI":"10.1073\/pnas.1711734114","volume":"114","author":"Z Liu","year":"2017","unstructured":"Liu, Z., Kurokawa, K., Zhang, F., Lee, J. J. & Miller, D. T. Imaging and quantifying ganglion cells and other transparent neurons in the living human retina. Proc. Natl. Acad. Sci. USA 114, 12803\u201312808. https:\/\/doi.org\/10.1073\/pnas.1711734114 (2017).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"71626_CR30","doi-asserted-by":"publisher","first-page":"8936","DOI":"10.1523\/JNEUROSCI.18-21-08936.1998","volume":"18","author":"CJ Jeon","year":"1998","unstructured":"Jeon, C. J., Strettoi, E. & Masland, R. H. The major cell populations of the mouse retina. J. Neurosci. 18, 8936\u20138946 (1998).","journal-title":"J. Neurosci."},{"key":"71626_CR31","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1006\/excr.1996.0240","volume":"226","author":"OS Frankfurt","year":"1996","unstructured":"Frankfurt, O. S., Robb, J. A., Sugarbaker, E. V. & Villa, L. Monoclonal antibody to single-stranded DNA is a specific and sensitive cellular marker of apoptosis. Exp. Cell Res. 226, 387\u2013397. https:\/\/doi.org\/10.1006\/excr.1996.0240 (1996).","journal-title":"Exp. Cell Res."},{"key":"71626_CR32","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671\u2013675 (2012).","journal-title":"Nat. Methods"},{"key":"71626_CR33","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1167\/iovs.17-22703","volume":"59","author":"S Sugita","year":"2018","unstructured":"Sugita, S., Makabe, K., Iwasaki, Y., Fujii, S. & Takahashi, M. Natural killer cell inhibition by HLA-E molecules on induced pluripotent stem cell-derived retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 59, 1719\u20131731. https:\/\/doi.org\/10.1167\/iovs.17-22703 (2018).","journal-title":"Invest. Ophthalmol. Vis. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-71626-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-71626-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-71626-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T19:23:28Z","timestamp":1670354608000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-71626-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,7]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["71626"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-71626-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,7]]},"assertion":[{"value":"29 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14700"}}