ALKBH5 exacerbates psoriatic dermatitis in mice by promoting angiogenesis

Abstract

Psoriasis is a chronic inflammatory skin disease, and its pathogenesis is largely modulated by abnormal angiogenesis. Previous research has indicated that AlkB homolog 5 (ALKBH5), an important demethylase affecting N⁶-methyladenosine (m⁶A) modification, plays a role in regulating angiogenesis in cardiovascular and eye diseases. Our present study found that ALKBH5 was upregulated and co-localized with cluster of differentiation 31 (CD31) in the skin of IMQ group compared with control group. ALKBH5-deficient mice decreased IMQ-induced psoriatic dermatitis and exhibited histological improvements, including decreased epidermal thickness, hyperkeratosis, numbers of dermal capillary vessels and inflammatory cell infiltration. ALKBH5-KO mice alleviated angiogenesis in psoriatic lesions by downregulating the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Additionally, the expression of ALKBH5 was significantly upregulated in IL-17A-induced human umbilical vein endothelial cells (HUVECs), which further promoted the expression of angiogenesis-related cytokines and endothelial cell proliferation. Cell proliferation and angiogenesis were suppressed in ALKBH5 knockdown group, whereas ALKBH5 overexpression promoted these processes. The regulation of angiogenesis in HUVECs by ALKBH5 was facilitated through the AKT-mTOR pathway. Collectively, ALKBH5 plays a pivotal role in psoriatic dermatitis and angiogenesis, which may offer a new potential targets for treating psoriasis.

Keywords

psoriasis / m ⁶A / ALKBH5 / angiogenesis / AKT/mTOR signaling pathway

References

[1] Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, Mehta NN, Finlay AY, Gottlieb AB. Psoriasis. Nat Rev Dis Primers 2016; 2(1): 16082

[2] Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker JNWN. Psoriasis. Lancet 2021; 397(10281): 1301–1315

[3] Crawshaw AA, Griffiths CE, Young HS. Investigational VEGF antagonists for psoriasis. Expert Opin Investig Drugs 2012; 21(1): 33–43

[4] Malecic N, Young HS. Novel investigational vascular endothelial growth factor (VEGF) receptor antagonists for psoriasis. Expert Opin Investig Drugs 2016; 25(4): 455–462

[5] Canavese M, Altruda F, Ruzicka T, Schauber J. Vascular endothelial growth factor (VEGF) in the pathogenesis of psoriasis—a possible target for novel therapies. J Dermatol Sci 2010; 58(3): 171–176

[6] Lee HJ, Hong YJ, Kim M. Angiogenesis in chronic inflammatory skin disorders. Int J Mol Sci 2021; 22(21): 12035

[7] Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT. Interleukin-17 promotes angiogenesis and tumor growth. Blood 2003; 101(7): 2620–2627

[8] Numasaki M, Watanabe M, Suzuki T, Takahashi H, Nakamura A, McAllister F, Hishinuma T, Goto J, Lotze MT, Kolls JK, Sasaki H. IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol 2005; 175(9): 6177–6189

[9] Karbach S, Croxford AL, Oelze M, Schüler R, Minwegen D, Wegner J, Koukes L, Yogev N, Nikolaev A, Reißig S, Ullmann A, Knorr M, Waldner M, Neurath MF, Li H, Wu Z, Brochhausen C, Scheller J, Rose-John S, Piotrowski C, Bechmann I, Radsak M, Wild P, Daiber A, von Stebut E, Wenzel P, Waisman A, Münzel T. Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease. Arterioscler Thromb Vasc Biol 2014; 34(12): 2658–2668

[10] Beringer A, Miossec P. IL-17 and TNF-α co-operation contributes to the proinflammatory response of hepatic stellate cells. Clin Exp Immunol 2019; 198(1): 111–120

[11] Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, Mineau F, Pelletier JP. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-β and TNF-α by human macrophages. J Immunol 1998; 160(7): 3513–3521

[12] Zhang J, Qiao Q, Liu M, He T, Shi J, Bai X, Zhang Y, Li Y, Cai W, Han S, Guan H, Hu D. IL-17 promotes scar formation by inducing macrophage infiltration. Am J Pathol 2018; 188(7): 1693–1702

[13] Huang Q, Duan L, Qian X, Fan J, Lv Z, Zhang X, Han J, Wu F, Guo M, Hu G, Du J, Chen C, Jin Y. IL-17 promotes angiogenic factors IL-6, IL-8, and Vegf production via Stat1 in lung adenocarcinoma. Sci Rep 2016; 6(1): 36551

[14] Ahn SH, Edwards AK, Singh SS, Young SL, Lessey BA, Tayade C. IL-17A contributes to the pathogenesis of endometriosis by triggering proinflammatory cytokines and angiogenic growth factors. J Immunol 2015; 195(6): 2591–2600

[15] Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell 2017; 169(7): 1187–1200

[16] Csepany T, Lin A, Baldick CJ Jr, Beemon K. Sequence specificity of mRNA N⁶-adenosine methyltransferase. J Biol Chem 1990; 265(33): 20117–20122

[17] Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m⁶A RNA methylomes revealed by m⁶A-seq. Nature 2012; 485(7397): 201–206

[18] Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 2012; 149(7): 1635–1646

[19] Liu J, Jia G. Methylation modifications in eukaryotic messenger RNA. J Genet Genomics 2014; 41(1): 21–33

[20] Fu Y, Dominissini D, Rechavi G, He C. Gene expression regulation mediated through reversible m⁶A RNA methylation. Nat Rev Genet 2014; 15(5): 293–306

[21] Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, Yang C, Chen Y. The role of m⁶A modification in the biological functions and diseases. Signal Transduct Target Ther 2021; 6(1): 74

[22] Falnes PØ, Johansen RF, Seeberg E. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature 2002; 419(6903): 178–182

[23] Rubio RM, Depledge DP, Bianco C, Thompson L, Mohr I. RNA m⁶A modification enzymes shape innate responses to DNA by regulating interferon β. Genes Dev 2018; 32(23-24): 1472–1484

[24] Zheng Q, Hou J, Zhou Y, Li Z, Cao X. The RNA helicase DDX46 inhibits innate immunity by entrapping m⁶A-demethylated antiviral transcripts in the nucleus. Nat Immunol 2017; 18(10): 1094–1103

[25] Liu B, Liu N, Zhu X, Yang L, Ye B, Li H, Zhu P, Lu T, Tian Y, Fan Z. Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m⁶A demethylation of Nr4a1 mRNA. Cell Mol Immunol 2021; 18(6): 1412–1424

[26] Zhou J, Zhang X, Hu J, Qu R, Yu Z, Xu H, Chen H, Yan L, Ding C, Zou Q, Ye Y, Wang Z, Flavell RA, Li HB. m⁶A demethylase ALKBH5 controls CD4⁺ T cell pathogenicity and promotes autoimmunity. Sci Adv 2021; 7(25): eabg0470

[27] Dong F, Qin X, Wang B, Li Q, Hu J, Cheng X, Guo D, Cheng F, Fang C, Tan Y, Yan H, He Y, Sun X, Yuan Y, Liu H, Li T, Zhao Y, Kang C, Wu X. ALKBH5 facilitates hypoxia-induced paraspeckle assembly and IL8 secretion to generate an immunosuppressive tumor microenvironment. Cancer Res 2021; 81(23): 5876–5888

[28] Shen W, Pu J, Zuo Z, Gu S, Sun J, Tan B, Wang L, Cheng J, Zuo Y. The RNA demethylase ALKBH5 promotes the progression and angiogenesis of lung cancer by regulating the stability of the LncRNA PVT1. Cancer Cell Int 2022; 22(1): 353

[29] He L, Liu L, Xu D, Tu Y, Yang C, Zhang M, Wang H, Nong X. Deficiency of N⁶-methyladenosine demethylase ALKBH5 alleviates ultraviolet B radiation-induced chronic actinic dermatitis via regulating pyroptosis. Inflammation 2024; 47(1): 159–172

[30] Huang X, Zhao Y, Liu D, Gu S, Liu Y, Khoong Y, Luo S, Zhang Z, Xia W, Wang M, Liang H, Li M, Li Q, Zan T. ALKBH5-mediated m⁶A demethylation fuels cutaneous wound re-epithelialization by enhancing PELI2 mRNA stability. Inflamm Regen 2023; 43(1): 36

[31] Sun RX, Zhu HJ, Zhang YR, Wang JN, Wang Y, Cao QC, Ji JD, Jiang C, Yuan ST, Chen X, Liu QH. ALKBH5 causes retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via the AKT/mTOR pathway. Cell Rep 2023; 42(7): 112779

[32] Ren Y, Dong H, Jin R, Jiang J, Zhang X. TRIM22 actives PI3K/Akt/mTOR pathway to promote psoriasis through enhancing cell proliferation and inflammation and inhibiting autophagy. Cutan Ocul Toxicol 2022; 41(4): 304–309

[33] Zhao Y, Hu J, Sun X, Yang K, Yang L, Kong L, Zhang B, Li F, Li C, Shi B, Hu K, Sun A, Ge J. Loss of m⁶A demethylase ALKBH5 promotes post-ischemic angiogenesis via post-transcriptional stabilization of WNT5A. Clin Transl Med 2021; 11(5): e402

[34] Wang YN, Jin HZ. Transcriptome-wide m⁶A methylation in skin lesions from patients with psoriasis vulgaris. Front Cell Dev Biol 2020; 8: 591629

[35] Yang L, Fu J, Han X, Zhang C, Xia L, Zhu R, Huang S, Xiao W, Yu H, Gao Y, Liang Q, Li W, Zhou Y. Hsa_circ_0004287 inhibits macrophage-mediated inflammation in an N⁶-methyladenosine-dependent manner in atopic dermatitis and psoriasis. J Allergy Clin Immunol 2022; 149(6): 2021–2033

[36] Xian J, Shang M, Dai Y, Wang Q, Long X, Li J, Cai Y, Xia C, Peng X. N⁶-methyladenosine-modified long non-coding RNA AGAP2–AS1 promotes psoriasis pathogenesis via miR-424-5p/AKT3 axis. J Dermatol Sci 2022; 105(1): 27–36

[37] Li N, Kang Y, Wang L, Huff S, Tang R, Hui H, Agrawal K, Gonzalez GM, Wang Y, Patel SP, Rana TM. ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc Natl Acad Sci USA 2020; 117(33): 20159–20170

[38] Vegfors J, Ekman AK, Stoll SW, Bivik Eding C, Enerbäck C. Psoriasin (S100A7) promotes stress-induced angiogenesis. Br J Dermatol 2016; 175(6): 1263–1273

[39] Hu X, Zou Y, Copland DA, Schewitz-Bowers LP, Li Y, Lait PJP, Stimpson M, Zhang Z, Guo S, Liang J, Chen T, Li JJ, Yuan S, Li S, Zhou P, Liu Y, Dick AD, Wen X, Lee RWJ, Wei L. Epigenetic drug screen identified IOX1 as an inhibitor of Th17-mediated inflammation through targeting TET2. EBioMedicine 2022; 86: 104333

[40] Wang H, Zhao S, Liu H, Liu Y, Zhang Z, Zhou Z, Wang P, Qi S, Xie J. ALKBH5 facilitates the progression of skin cutaneous melanoma via mediating ABCA1 demethylation and modulating autophagy in an m⁶A-dependent manner. Int J Biol Sci 2024; 20(5): 1729–1743

[41] Wang J, Zhou L, Hou H, Li J, Zhao X, Li J, Li J, Niu X, Hou R, Zhang K. IL-17A is involved in the hyperplasia of blood vessels in local lesions of psoriasis by inhibiting autophagy. J Cosmet Dermatol 2024; 23(1): 326–338

[42] Li N, Luo R, Zhang W, Wu Y, Hu C, Liu M, Jiang D, Jiang Z, Zhao X, Wang Y, Li Q. IL-17A promotes endothelial cell senescence by up-regulating the expression of FTO through activating JNK signal pathway. Biogerontology 2023; 24(1): 99–110

[43] Zhang S, Zhang J, Yu J, Chen X, Zhang F, Wei W, Zhang L, Chen W, Lin N, Wu Y. Hyperforin ameliorates imiquimod-induced psoriasis-like murine skin inflammation by modulating IL-17A-producing γδT cells. Front Immunol 2021; 12: 635076

[44] Ding C, Xu H, Yu Z, Roulis M, Qu R, Zhou J, Oh J, Crawford J, Gao Y, Jackson R, Sefik E, Li S, Wei Z, Skadow M, Yin Z, Ouyang X, Wang L, Zou Q, Su B, Hu W, Flavell RA, Li HB. RNA m⁶A demethylase ALKBH5 regulates the development of γδ T cells. Proc Natl Acad Sci USA 2022; 119(33): e2203318119

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