Phosphatidylserine Topically Attenuates Imiquimod-induced Psoriasis Through Inflammation Inhibition in Mice

Abstract

Background Psoriasis is a chronic skin condition that is associated with persistent inflammation and skin lesions. Topical therapy has been a promising approach to the alleviation of psoriasis through the application of anti-inflammatory agents. Phosphatidylserine (PS) administration has shown anti-inflammatory effects in the trials. Consequently, the objective of this study was to evaluate the effects of topical PS on the potential improvement of an imiquimod (IMQ)-induced psoriasis model. Additionally, cyclosporine A was utilized as a comparative anti-psoriatic agent in our study.

Methods The psoriasis model was established by topically applying IMQ to the dorsal skin of mice once daily for five consecutive days. The efficacy of topical PS was assessed using the Psoriasis Area and Severity Index (PASI) score to evaluate skin lesions. Subsequently, the skin samples were analyzed using Baker’s scoring system, Masson’s trichrome staining, immunohistochemistry, and real-time PCR analysis.

Results IMQ-induced plaque-type psoriasis resulted in a significant increase (P<0.05) in dermal thickness, hyperkeratosis, PASI score, and inflammatory cytokines at the lesion site. The topical PS and cyclosporine A significantly (P<0.05) reduced PASI score and dermal thickness, while also alleviating erythema and scaling when compared to untreated mice. Furthermore, biomolecular assessments revealed that PS significantly (P<0.05) inhibited the gene expression of IL-17, IL-23, and TNF-α cytokines in the IMQ-induced lesions.

Conclusion Topical PS may pointedly alleviate psoriasis through the inhibition of inflammation. The beneficial effects of the PS recommend further investigation in both experimental and clinical studies in the control of skin psoriasis.

Keywords

phospholipid - inflammation - skin disease - psoriasis - animal

Publication History

Received: 06 June 2024

Accepted: 16 September 2024

Article published online:
15 October 2024

• References

• 1 Medovic MV, Jakovljevic VL, Zivkovic VI. et al. Psoriasis between Autoimmunity and Oxidative Stress: Changes Induced by Different Therapeutic Approaches. Oxidative Medicine and Cellular Longevity. 2022 2022. 2249834
• 2 Bruni F, Alessandrini A, Starace M. et al. Clinical and trichoscopic features in various forms of scalp psoriasis. Journal of the European Academy of Dermatology and Venereology 2021; 35: 1830-1837
• 3 Fania L, Didona D, Di Pietro FR. et al. Cutaneous squamous cell carcinoma: From pathophysiology to novel therapeutic approaches. Biomedicines 2021; 9: 171
• 4 Yamanaka K, Yamamoto O, Honda T. Pathophysiology of psoriasis: a review. The Journal of Dermatology 2021; 48: 722-31
• 5 Ly K, Smith MP, Thibodeaux Q. et al. Anti IL-17 in psoriasis. Expert review of clinical immunology 2019; 15: 1185-94
• 6 Oliveira DG, Faria R, Torres T. An overview of bimekizumab for the treatment of psoriatic arthritis: the evidence so far. Drug design, development and therapy 2021; 15: 1045
• 7 Nadeem A, Ahmad SF, Al-Harbi NO. et al. Bruton’s tyrosine kinase inhibitor suppresses imiquimod-induced psoriasis-like inflammation in mice through regulation of IL-23/IL-17A in innate immune cells. International Immunopharmacology 2020; 80: 106215
• 8 Alzahrani KS, Nadeem A, Ahmad SF. et al. Inhibition of spleen tyrosine kinase attenuates psoriasis-like inflammation in mice through blockade of dendritic cell-Th17 inflammation axis. Biomedicine & Pharmacotherapy 2019; 111: 347-58
• 9 Eyerich K, Weisenseel P, Pinter A. et al. Protocol: IL-23 blockade with guselkumab potentially modifies psoriasis pathogenesis: rationale and study protocol of a phase 3b, randomised, double-blind, multicentre study in participants with moderate-to-severe plaque-type psoriasis. (GUIDE) BMJ Open 2021; 11: e049822
• 10 Boehncke W-H, Brembilla NC. Autoreactive T-lymphocytes in inflammatory skin diseases. Frontiers in immunology 2019; 10: 1198
• 11 Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: a review. Jama 2020; 323: 1945-1960
• 12 Devaux S, Castela A, Archier E. et al. Adherence to topical treatment in psoriasis: a systematic literature review. Journal of the European Academy of Dermatology and Venereology 2012; 26: 61-67
• 13 Feldman SR, Goffe B, Rice G. et al. The challenge of managing psoriasis: unmet medical needs and stakeholder perspectives. American health & drug benefits 2016; 9: 504
• 14 Glade MJ, Smith K. Phosphatidylserine and the human brain. Nutrition 2015; 31: 781-786
• 15 Zhang Y, Yang L, Guo L. Effect of phosphatidylserine on memory in patients and rats with Alzheimer’s disease. Genet Mol Res 2015; 14: 9325-9333
• 16 He X, Hong W, Yang J. et al. Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine. Signal transduction and targeted therapy 2021; 6: 270
• 17 Komeili M, Noorbakhsh F, Esmaili J. et al. Combination therapy of phosphatidylserine liposome with cyclosporine A improves nephrotoxicity and attenuates delayed-type hypersensitivity response. Life Sciences. 2021 265. 118780
• 18 Nazeri SA, Rezayat SM, Amani A. et al. A novel formulation of cyclosporine A/phosphatidylserine-containing liposome using remote loading method: Potential product for immunosuppressive effects. Journal of Drug Delivery Science and Technology 2022; 77: 103902
• 19 Saffari PM, Alijanpour S, Takzaree N. et al. Metformin loaded phosphatidylserine nanoliposomes improve memory deficit and reduce neuroinflammation in streptozotocin-induced Alzheimer's disease model. Life Sciences 2020; 255: 117861
• 20 Bevers EM, Williamson PL. Getting to the outer leaflet: physiology of phosphatidylserine exposure at the plasma membrane. Physiological reviews 2016; 96: 605-645
• 21 Birge R, Boeltz S, Kumar S. et al. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death & Differentiation 2016; 23: 962-978
• 22 Hoffmann PR, Kench JA, Vondracek A. et al. Interaction between phosphatidylserine and the phosphatidylserine receptor inhibits immune responses in vivo. The Journal of Immunology 2005; 174: 1393-1404
• 23 Zamanian G, Partoazar A, Tavangar SM. et al. Effect of phosphatidylserine on cirrhosis-induced hepatic encephalopathy: response to acute endotoxemia in cirrhotic rats. Life sciences 2020; 253: 117606
• 24 Al-Harbi NO, Ahmad SF, Almutairi M. et al. Lck signaling inhibition causes improvement in clinical features of psoriatic inflammation through reduction in inflammatory cytokines in CD4+T cells in imiquimod mouse model. Cellular Immunology 2022; 376: 104531
• 25 Kim HY, Huang BX, Spector AA. Phosphatidylserine in the brain: metabolism and function. Prog Lipid Res 2014; 56: 1-18
• 26 Saffari PM, Asili P, Eshraghi S. et al. Phosphatidylserine accelerates wound healing and reduces necrosis in the rats: Growth factor activation. Clinical and Experimental Pharmacology and Physiology 2024; 51: e13849
• 27 Rajagopalan M, Saraswat A, Chandrashekar BS. et al. Role of Cyclosporine (CsA) in Immuno-dermatological Conditions. Indian Dermatol Online J 2022; 13: 585-599
• 28 Sadeghi S, Kalantari Y, Seirafianpour F. et al. A systematic review of the efficacy and safety of topical cyclosporine in dermatology. Dermatol Ther 2022; 35: e15490
• 29 van der Fits L, Mourits S, Voerman JS. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 2009; 182: 5836-5845
• 30 Goudarzi R, Kim M-H, Partoazar A. Anti-psoriatic characteristics of ROCEN (topical Arthrocen) in comparison with Cyclosporine A in a murine model. BMC Complementary Medicine and Therapies 2024; 24: 100
• 31 Costache DO, Feroiu O, Ghilencea A. et al. Skin Inflammation Modulation via TNF-alpha, IL-17, and IL-12 Family Inhibitors Therapy and Cancer Control in Patients with Psoriasis. Int J Mol Sci 2022; 23: 5198
• 32 Li SJ, Perez-Chada LM, Merola JF. TNF Inhibitor-Induced Psoriasis: Proposed Algorithm for Treatment and Management. J Psoriasis Psoriatic Arthritis 2019; 4: 70-80
• 33 Lowes MA, Russell CB, Martin DA. et al. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends in immunology 2013; 34: 174-181
• 34 Boutet MA, Nerviani A, Gallo Afflitto G. et al. Role of the IL-23/IL-17 Axis in Psoriasis and Psoriatic Arthritis: The Clinical Importance of Its Divergence in Skin and Joints. Int J Mol Sci 2018; 19: 530
• 35 Eskandarynasab M, Doustimotlagh AH, Takzaree N. et al. Phosphatidylserine nanoliposomes inhibit glucocorticoid-induced osteoporosis: A potential combination therapy with alendronate. Life sciences 2020; 257: 118033
• 36 Eskandarynasab M, Etemad-Moghadam S, Alaeddini M. et al. Novel osteoprotective nanocochleate formulation: a dual combination therapy-codelivery system against glucocorticoid induced osteoporosis. Nanomedicine: Nanotechnology, Biology and Medicine 2020; 29: 102273
• 37 Zeini MS, Haddadi N-S, Shayan M. et al. Losartan ointment attenuates imiquimod-induced psoriasis-like inflammation. International Immunopharmacology 2021; 100: 108160
• 38 Van Der Fits L, Mourits S, Voerman JS. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. The Journal of Immunology 2009; 182: 5836-5845
• 39 Baker B, Brent L, Valdimarsson H. et al. Is epidermal cell proliferation in psoriatic skin grafts on nude mice driven by T-cell derived cytokines?. British journal of Dermatology 1992; 126: 105-110
• 40 Valizadeh Z, Beheshti M, Ashrafi F. et al. Response to Treatment in 4T1 Tumor Following Exposure to Paclitaxel and Doxorubicin Based on Antiangiogenic Effects. Basic & Clinical Cancer Research 2021; 13: 119-126