Chemerin Exacerbates Psoriasis by Stimulating Keratinocyte Proliferation and Cytokine Production

Abstract

Objective

Psoriasis is often combined with metabolic abnormalities, such as obesity and diabetes. The upregulation of chemerin, which is an essential protein produced primarily from white fat, is strongly correlated to the development of psoriasis. However, there is no clarification on its exact function and mechanism in disease pathogenesis. The present study aims to determine its function and mechanism in disease pathogenesis.

Methods

The present study used a psoriasislike inflammatory cell model and imiquimod (IMQ)-induced mouse model to confirm whether chemerin is upregulated in psoriasis patients.

Results

Chemerin enhanced the keratinocyte proliferation, inflammatory cytokine secretion, and activation of the MAPK signaling pathway. Crucially, the intraperitoneal injection of neutralizing anti-chemerin antibody (ChAb) diminished the epidermal proliferation and inflammation in the IMQ-induced mouse model.

Conclusion

The present results indicate that chemerin promotes keratinocyte proliferation, and enhances the production of inflammatory cytokines, thereby aggravating the psoriasis. Thus, chemerin can be a prospective target for the treatment of psoriasis.

Keywords

psoriasis / keratinocyte / chemerin / proliferation / inflammation

References

[1] BoehnckeW, SchönMP. Psoriasis. Lancet, 2015, 386(9997): 983-994

[2] ArmstrongAW, ReadC. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA, 2020, 323(19): 1945-1960

[3] RendonA, SchäkelK. Psoriasis Pathogenesis and Treatment. Int J Mol Sci, 2019, 20(6): 1475

[4] DavidoviciBB, SattarN, PrinzJ, et al.. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol, 2010, 130(7): 1785-1796

[5] SalesR, TorresT. Psoriasis and metabolic syndrome. Acta Dermatovenerol Croat, 2014, 22(3): 169-174

[6] ChiricozziA, RaimondoA, LemboS, et al.. Crosstalk between skin inflammation and adipose tissue-derived products: pathogenic evidence linking psoriasis to increased adiposity. Expert Rev Clin Immunol, 2016, 12(12): 1299-1308

[7] AcewiczM, KasackaI. Chemerin activity in selected pathological states of human body — A systematic review. Adv Med Sci, 2021, 66(2): 270-278

[8] NagpalS, PatelS, JacobeH, et al.. Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin. J Invest Dermatol, 1997, 109(1): 91-95

[9] MatternA, ZellmannT, Beck-SickingerAG. Processing, signaling, and physiological function of chemerin. IUBMB Life, 2014, 66(1): 19-26

[10] KuklaM, AdamekB, WalugaM, et al.. Hepatic chemerin and chemokine-like receptor 1 expression in patients with chronic hepatitis C. Biomed Res Int, 2014, 2014: 517820

[11] BoyukB, GuzelEC, AtalayH, et al.. Relationship between plasma chemerin levels and disease severity in COPD patients. Clin Respir J, 2015, 9(4): 468-474

[12] AdrychK, StojekM, SmoczynskiM, et al.. Increased serum chemerin concentration in patients with chronic pancreatitis. Dig Liver Dis, 2012, 44(5): 393-397

[13] BuechlerC. Chemerin, a novel player in inflammatory bowel disease. Cell Mol Immunol, 2014, 11(4): 315-316

[14] LehrkeM, BeckerA, GreifM, et al.. Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis. Eur J Endocrinol, 2009, 161(2): 339-344

[15] MarianiF, RoncucciL. Chemerin/chemR23 axis in inflammation onset and resolution. Inflamm Res, 2015, 64(2): 85-95

[16] ParoliniS, SantoroA, MarcenaroE, et al.. The role of chemerin in the colocalization of NK and dendritic cell subsets into inflamed tissues. Blood, 2007, 109(9): 3625-3632

[17] FischerTF, Beck-SickingerAG. Chemerin-exploring a versatile adipokine. Biol Chem, 2022, 403(7): 625-642

[18] BaiF, ZhengW, DongY, et al.. Serum levels of adipokines and cytokines in psoriasis patients: a systematic review and meta-analysis. Oncotarget, 2018, 9(1): 1266-1278

[19] GisondiP, LoraV, BonauguriC, et al.. Serum chemerin is increased in patients with chronic plaque psoriasis and normalizes following treatment with infliximab. Br J Dermatol, 2013, 168(4): 749-755

[20] Skrzeczynska-MoncznikJ, WawroK, StefanskaA, et al.. Potential role of chemerin in recruitment of plasmacytoid dendritic cells to diseased skin. Biochem Biophys Res Commun, 2009, 380(2): 323-327

[21] AlbanesiC, ScarponiC, PallottaS, et al.. Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment. J Exp Med, 2009, 206(1): 249-258

[22] BanasM, ZegarA, KwitniewskiM, et al.. The expression and regulation of chemerin in the epidermis. PLoS One, 2015, 10(2): e117830

[23] GaoC, ShiJ, ZhangJ, et al.. Chemerin promotes proliferation and migration of ovarian cancer cells by upregulating expression of PD-L1. J Zhejiang Univ Sci B, 2022, 23(2): 164-170

[24] BonifaceK, BernardFX, GarciaM, et al.. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol, 2005, 174(6): 3695-3702

[25] MulcahyME, LeechJM, RenauldJC, et al.. Interleukin-22 regulates antimicrobial peptide expression and keratinocyte differentiation to control Staphylococcus aureus colonization of the nasal mucosa. Mucosal Immunol, 2016, 9(6): 1429-1441

[26] KanekoK, MiyabeY, TakayasuA, et al.. Chemerin activates fibroblast-like synoviocytes in patients with rheumatoid arthritis. Arthritis Res Ther, 2011, 13(5): R158

[27] WangY, HuoJ, ZhangD, et al.. Chemerin/ChemR23 axis triggers an inflammatory response in keratinocytes through ROS-sirt1-NF-κB signaling. J Cell Biochem, 2019, 120(4): 6459-6470

[28] ArthurJS, DarraghJ. Signaling downstream of p38 in psoriasis. J Invest Dermatol, 2006, 126(8): 1689-1691

[29] SunY, ZhangJ, ZhaiT, et al.. CCN1 promotes IL-1beta production in keratinocytes by activating p38 MAPK signaling in psoriasis. Sci Rep, 2017, 7: 43310

[30] YangG, LiS, YangY, et al.. Nobiletin and 5-Hydroxy-6,7,8,3′,4′-pentamethoxyflavone Ameliorate 12-O-Te-tradecanoylphorbol-13-acetate-Induced Psoriasis-Like Mouse Skin Lesions by Regulating the Expression of Ki-67 and Proliferating Cell Nuclear Antigen and the Differentiation of CD4(+) T Cells through Mitogen-Activated Protein Kinase Signaling Pathways. J Agric Food Chem, 2018, 66(31): 8299-8306

[31] Soegaard-MadsenL, JohansenC, IversenL, et al.. Adalimumab therapy rapidly inhibits p38 mitogen-activated protein kinase activity in lesional psoriatic skin preceding clinical improvement. Br J Dermatol, 2010, 162(6): 1216-1223