Inhibition of JNK ameliorates rod photoreceptor degeneration in a mouse model of retinitis pigmentosa.
JNK
inflammation
microglia
photoreceptor degeneration
Journal
FEBS letters
ISSN: 1873-3468
Titre abrégé: FEBS Lett
Pays: England
ID NLM: 0155157
Informations de publication
Date de publication:
15 Jul 2024
15 Jul 2024
Historique:
revised:
01
06
2024
received:
18
03
2024
accepted:
09
06
2024
medline:
16
7
2024
pubmed:
16
7
2024
entrez:
16
7
2024
Statut:
aheadofprint
Résumé
Retinitis pigmentosa (RP) is an inherited eye disease that causes progressive vision loss. Microglial activation and inflammation play essential roles in photoreceptor degeneration in RP, although the underlying mechanisms remain unclear. Here, we examined the progressive degeneration of photoreceptors in rd1 mice, a mouse model of RP. We investigated the molecular changes in various retinal cells in rd1 mice using single-cell RNA sequencing and found that potentiation of JNK signaling is associated with photoreceptor degeneration in RP. Moreover, inflammation-related molecules, which function downstream of JNK, are elevated in RP. Furthermore, inhibiting JNK alleviates microglial activation and rescues photoreceptor degeneration in rd1 mice. Thus, our findings suggest that targeting JNK is a promising approach for slowing RP progression.
Identifiants
pubmed: 39010325
doi: 10.1002/1873-3468.14978
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Guangdong Provincial Fund for Basic and Applied Basic Research
ID : 2021A1515111079
Organisme : Guangdong Provincial Fund for Basic and Applied Basic Research
ID : 2019B1515130004
Organisme : National Key R&D Program of China
ID : 2021YFE0203000
Organisme : Shenzhen Fundamental Research Program
ID : JCYJ20220531100217038
Organisme : Shenzhen Fundamental Research Program
ID : JCYJ20220818100800001
Organisme : Shenzhen Fundamental Research Program
ID : JCYJ20200109115631248
Organisme : Shenzhen Fundamental Research Program
ID : ZDSYS20200828154800001
Organisme : NSFC/RGC Joint Research Scheme
ID : 32061160472
Informations de copyright
© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
Hartong DT, Berson EL and Dryja TP (2006) Retinitis pigmentosa. Lancet 368, 1795–1809.
Ortega JT and Jastrzebska B (2021) Neuroinflammation as a therapeutic target in retinitis pigmentosa and quercetin as its potential modulator. Pharmaceutics 13, 1935.
Zhao L, Hou C and Yan N (2022) Neuroinflammation in retinitis pigmentosa: therapies targeting the innate immune system. Front Immunol 13, 1059947.
Zhou T, Huang Z, Sun X, Zhu X, Zhou L, Li M, Cheng B, Liu X and He C (2017) Microglia polarization with M1/M2 phenotype changes in rd1 mouse model of retinal degeneration. Front Neuroanat 11, 77.
Zhao L, Zabel MK, Wang X, Ma W, Shah P, Fariss RN, Qian H, Parkhurst CN, Gan WB and Wong WT (2015) Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Mol Med 7, 1179–1197.
Manning AM and Davis RJ (2003) Targeting JNK for therapeutic benefit: from junk to gold? Nat Rev Drug Discov 2, 554–565.
Dhanasekaran DN and Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27, 6245–6251.
Waetzig V, Czeloth K, Hidding U, Mielke K, Kanzow M, Brecht S, Goetz M, Lucius R, Herdegen T and Hanisch UK (2005) c‐Jun N‐terminal kinases (JNKs) mediate pro‐inflammatory actions of microglia. Glia 50, 235–246.
Yang C, Yu L, Kong L, Ma R, Zhang J, Zhu Q, Zhu J and Hao D (2014) Pyrroloquinoline quinone (PQQ) inhibits lipopolysaccharide induced inflammation in part via downregulated NF‐kappaB and p38/JNK activation in microglial and attenuates microglia activation in lipopolysaccharide treatment mice. PLoS One 9, e109502.
Kacimi R, Giffard RG and Yenari MA (2011) Endotoxin‐activated microglia injure brain derived endothelial cells via NF‐kappaB, JAK‐STAT and JNK stress kinase pathways. J Inflamm (Lond) 8, 7.
Cai B, Seong KJ, Bae SW, Kook MS, Chun C, Lee JH, Choi WS, Jung JY and Kim WJ (2019) Water‐soluble arginyl‐diosgenin analog attenuates hippocampal neurogenesis impairment through blocking microglial activation underlying NF‐kappaB and JNK MAPK signaling in adult mice challenged by LPS. Mol Neurobiol 56, 6218–6238.
Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, Rakic P and Flavell RA (2004) JNK‐mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. Proc Natl Acad Sci USA 101, 665–670.
Wagner EF and Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9, 537–549.
Tao L, He D, Liao C, Cai B, Chen C, Wang Y, Chen J, Liu Z and Wu Y (2022) Repressing c‐Jun N‐terminal kinase signaling mitigates retinal pigment epithelium degeneration in mice with failure to clear all‐trans‐retinal. Exp Eye Res 214, 108877.
Guma M, Rius J, Duong‐Polk KX, Haddad GG, Lindsey JD and Karin M (2009) Genetic and pharmacological inhibition of JNK ameliorates hypoxia‐induced retinopathy through interference with VEGF expression. Proc Natl Acad Sci USA 106, 8760–8765.
Du H, Sun X, Guma M, Luo J, Ouyang H, Zhang X, Zeng J, Quach J, Nguyen DH, Shaw PX et al. (2013) JNK inhibition reduces apoptosis and neovascularization in a murine model of age‐related macular degeneration. Proc Natl Acad Sci USA 110, 2377–2382.
Liao C, Cai B, Feng Y, Chen J, Wu Y, Zhuang J, Liu Z and Wu Y (2020) Activation of JNK signaling promotes all‐trans‐retinal‐induced photoreceptor apoptosis in mice. J Biol Chem 295, 6958–6971.
Pittler SJ and Baehr W (1991) Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta‐subunit gene of the rd mouse. Proc Natl Acad Sci USA 88, 8322–8326.
Sancho‐Pelluz J, Arango‐Gonzalez B, Kustermann S, Romero FJ, van Veen T, Zrenner E, Ekstrom P and Paquet‐Durand F (2008) Photoreceptor cell death mechanisms in inherited retinal degeneration. Mol Neurobiol 38, 253–269.
Strettoi E, Porciatti V, Falsini B, Pignatelli V and Rossi C (2002) Morphological and functional abnormalities in the inner retina of the rd/rd mouse. J Neurosci 22, 5492–5504.
Punzo C and Cepko C (2007) Cellular responses to photoreceptor death in the rd1 mouse model of retinal degeneration. Invest Ophthalmol Vis Sci 48, 849–857.
Bighinati A, Adani E, Stanzani A, D'Alessandro S and Marigo V (2024) Molecular mechanisms underlying inherited photoreceptor degeneration as targets for therapeutic intervention. Front Cell Neurosci 18, 1343544.
Ventura JJ, Kennedy NJ, Lamb JA, Flavell RA and Davis RJ (2003) c‐Jun NH(2)‐terminal kinase is essential for the regulation of AP‐1 by tumor necrosis factor. Mol Cell Biol 23, 2871–2882.
Grynberg K, Ma FY and Nikolic‐Paterson DJ (2017) The JNK signaling pathway in renal fibrosis. Front Physiol 8, 829.
Hamel C (2006) Retinitis pigmentosa. Orphanet J Rare Dis 1, 40.
Shintani K, Shechtman DL and Gurwood AS (2009) Review and update: current treatment trends for patients with retinitis pigmentosa. Optometry 80, 384–401.
Cross N, van Steen C, Zegaoui Y, Satherley A and Angelillo L (2022) Current and future treatment of retinitis pigmentosa. Clin Ophthalmol 16, 2909–2921.
Narayan DS, Wood JP, Chidlow G and Casson RJ (2016) A review of the mechanisms of cone degeneration in retinitis pigmentosa. Acta Ophthalmol 94, 748–754.
Han J, Dinculescu A, Dai X, Du W, Smith WC and Pang J (2013) Review: the history and role of naturally occurring mouse models with Pde6b mutations. Mol Vis 19, 2579–2589.
Strettoi E and Pignatelli V (2000) Modifications of retinal neurons in a mouse model of retinitis pigmentosa. Proc Natl Acad Sci USA 97, 11020–11025.
Sanges D, Comitato A, Tammaro R and Marigo V (2006) Apoptosis in retinal degeneration involves cross‐talk between apoptosis‐inducing factor (AIF) and caspase‐12 and is blocked by calpain inhibitors. Proc Natl Acad Sci USA 103, 17366–17371.
Lin B, Masland RH and Strettoi E (2009) Remodeling of cone photoreceptor cells after rod degeneration in rd mice. Exp Eye Res 88, 589–599.
Jones BW, Watt CB, Frederick JM, Baehr W, Chen CK, Levine EM, Milam AH, Lavail MM and Marc RE (2003) Retinal remodeling triggered by photoreceptor degenerations. J Comp Neurol 464, 1–16.
Vecino E, Rodriguez FD, Ruzafa N, Pereiro X and Sharma SC (2016) Glia‐neuron interactions in the mammalian retina. Prog Retin Eye Res 51, 1–40.
Murenu E, Gerhardt MJ, Biel M and Michalakis S (2022) More than meets the eye: the role of microglia in healthy and diseased retina. Front Immunol 13, 1006897.
Silverman SM and Wong WT (2018) Microglia in the retina: roles in development, maturity, and disease. Annu Rev Vis Sci 4, 45–77.
Karlstetter M, Scholz R, Rutar M, Wong WT, Provis JM and Langmann T (2015) Retinal microglia: just bystander or target for therapy? Prog Retin Eye Res 45, 30–57.
Langmann T (2007) Microglia activation in retinal degeneration. J Leukoc Biol 81, 1345–1351.
Zeiss CJ and Johnson EA (2004) Proliferation of microglia, but not photoreceptors, in the outer nuclear layer of the rd‐1 mouse. Invest Ophthalmol Vis Sci 45, 971–976.
Gupta N, Brown KE and Milam AH (2003) Activated microglia in human retinitis pigmentosa, late‐onset retinal degeneration, and age‐related macular degeneration. Exp Eye Res 76, 463–471.
Zeng HY, Zhu XA, Zhang C, Yang LP, Wu LM and Tso MO (2005) Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice. Invest Ophthalmol Vis Sci 46, 2992–2999.
Viringipurampeer IA, Metcalfe AL, Bashar AE, Sivak O, Yanai A, Mohammadi Z, Moritz OL, Gregory‐Evans CY and Gregory‐Evans K (2016) NLRP3 inflammasome activation drives bystander cone photoreceptor cell death in a P23H rhodopsin model of retinal degeneration. Hum Mol Genet 25, 1501–1516.
Noailles A, Fernandez‐Sanchez L, Lax P and Cuenca N (2014) Microglia activation in a model of retinal degeneration and TUDCA neuroprotective effects. J Neuroinflammation 11, 186.
Roesch K, Stadler MB and Cepko CL (2012) Gene expression changes within muller glial cells in retinitis pigmentosa. Mol Vis 18, 1197–1214.
Roche SL, Ruiz‐Lopez AM, Moloney JN, Byrne AM and Cotter TG (2018) Microglial‐induced muller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa. Glia 66, 295–310.
Blank T, Goldmann T, Koch M, Amann L, Schon C, Bonin M, Pang S, Prinz M, Burnet M, Wagner JE et al. (2017) Early microglia activation precedes photoreceptor degeneration in a mouse model of CNGB1‐linked retinitis pigmentosa. Front Immunol 8, 1930.
Rashid K, Akhtar‐Schaefer I and Langmann T (2019) Microglia in retinal degeneration. Front Immunol 10, 1975.
Wang M, Wang X, Zhao L, Ma W, Rodriguez IR, Fariss RN and Wong WT (2014) Macroglia‐microglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J Neurosci 34, 3793–3806.
Peng B, Xiao J, Wang K, So KF, Tipoe GL and Lin B (2014) Suppression of microglial activation is neuroprotective in a mouse model of human retinitis pigmentosa. J Neurosci 34, 8139–8150.
Grotegut P, Perumal N, Kuehn S, Smit A, Dick HB, Grus FH and Joachim SC (2020) Minocycline reduces inflammatory response and cell death in a S100B retina degeneration model. J Neuroinflammation 17, 375.
Wang SK, Xue Y and Cepko CL (2021) Augmentation of CD47/SIRPalpha signaling protects cones in genetic models of retinal degeneration. JCI Insight 6, e150796.
Wang SK, Xue Y, Rana P, Hong CM and Cepko CL (2019) Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa. Proc Natl Acad Sci USA 116, 10140–10149.
Okunuki Y, Mukai R, Pearsall EA, Klokman G, Husain D, Park DH, Korobkina E, Weiner HL, Butovsky O, Ksander BR et al. (2018) Microglia inhibit photoreceptor cell death and regulate immune cell infiltration in response to retinal detachment. Proc Natl Acad Sci USA 115, E6264–E6273.
O'Koren EG, Yu C, Klingeborn M, Wong AYW, Prigge CL, Mathew R, Kalnitsky J, Msallam RA, Silvin A, Kay JN et al. (2019) Microglial function is distinct in different anatomical locations during retinal homeostasis and degeneration. Immunity 50, 723–737.e7.
Kaur G and Singh NK (2021) The role of inflammation in retinal neurodegeneration and degenerative diseases. Int J Mol Sci 23, 386.
Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y, Hisatomi T, Enaida H and Ishibashi T (2013) Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology 120, 100–105.
Wang Y, Yin Z, Gao L, Sun D, Hu X, Xue L, Dai J, Zeng Y, Chen S, Pan B et al. (2017) Curcumin delays retinal degeneration by regulating microglia activation in the retina of rd1 mice. Cell Physiol Biochem 44, 479–493.
Guadagni V, Biagioni M, Novelli E, Aretini P, Mazzanti CM and Strettoi E (2019) Rescuing cones and daylight vision in retinitis pigmentosa mice. FASEB J 33, 10177–10192.
Guo C, Otani A, Oishi A, Kojima H, Makiyama Y, Nakagawa S and Yoshimura N (2012) Knockout of ccr2 alleviates photoreceptor cell death in a model of retinitis pigmentosa. Exp Eye Res 104, 39–47.
Sanchez‐Cruz A, Mendez AC, Lizasoain I, de la Villa P, de la Rosa EJ and Hernandez‐Sanchez C (2021) Tlr2 gene deletion delays retinal degeneration in two genetically distinct mouse models of retinitis pigmentosa. Int J Mol Sci 22, 7815.
Yang H, Zhang H and Li X (2024) Navigating the future of retinitis pigmentosa treatments: a comprehensive analysis of therapeutic approaches in rd10 mice. Neurobiol Dis 193, 106436.
Mercau ME, Akalu YT, Mazzoni F, Gyimesi G, Alberto EJ, Kong Y, Hafler BP, Finnemann SC, Rothlin CV and Ghosh S (2023) Inflammation of the retinal pigment epithelium drives early‐onset photoreceptor degeneration in Mertk‐associated retinitis pigmentosa. Sci Adv 9, eade9459.
Kim BJ, Silverman SM, Liu Y, Wordinger RJ, Pang IH and Clark AF (2016) In vitro and in vivo neuroprotective effects of cJun N‐terminal kinase inhibitors on retinal ganglion cells. Mol Neurodegener 11, 30.
Solas M, Vela S, Smerdou C, Martisova E, Martinez‐Valbuena I, Luquin MR and Ramirez MJ (2023) JNK activation in Alzheimer's disease is driven by amyloid beta and is associated with tau pathology. ACS Chem Neurosci 14, 1524–1534.
Chang B, Hawes NL, Pardue MT, German AM, Hurd RE, Davisson MT, Nusinowitz S, Rengarajan K, Boyd AP, Sidney SS et al. (2007) Two mouse retinal degenerations caused by missense mutations in the beta‐subunit of rod cGMP phosphodiesterase gene. Vis Res 47, 624–633.
Sakami S, Maeda T, Bereta G, Okano K, Golczak M, Sumaroka A, Roman AJ, Cideciyan AV, Jacobson SG and Palczewski K (2011) Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations. J Biol Chem 286, 10551–10567.
Lem J, Krasnoperova NV, Calvert PD, Kosaras B, Cameron DA, Nicolo M, Makino CL and Sidman RL (1999) Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc Natl Acad Sci USA 96, 736–741.