Skip to main content
Top
Published in: Inflammation Research 1/2021

01-01-2021 | Vulgar Psoriasis | Original Research Paper

The efficacy of in vivo administration of Apremilast on mesenchymal stem cells derived from psoriatic patients

Authors: Anna Campanati, Miriam Caffarini, Federico Diotallevi, Giulia Radi, Guendalina Lucarini, Mariangela Di Vincenzo, Monia Orciani, Annamaria Offidani

Published in: Inflammation Research | Issue 1/2021

Login to get access

Abstract

Introduction

Psoriasis cellular hallmarks, such as the imbalance between Th1/Th17 and Th2 cytokines and the dysregulated expression of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase, (iNOS) and indoleamine 2,3-dioxygenase (IDO), are all detectable in mesenchymal stem cells (MSCs) suggesting that psoriasis originates at mesenchymal level. Aim of the study: In this scenario, MSCs may become the new therapeutic target and interest in the effects of traditionally used drugs, such as Apremilast, on MSCs has greatly increased.

Materials and Methods

MSCs from control subjects (C-MSCs) and from psoriatic patients before (PsO MSCs T0) and after in vivo treatment with Apremilast (PsO-MSCs T12) were isolated and characterized; subsequently, the effects of Apremilast on VEGF, iNOS and IDO expression were evaluated by immunocytochemistry (ICC). The expression of VEGF, iNOS and IDO was also detected in skin sections by immunohistochemistry (IHC).

Results

The results indicate that in vivo administration of Apremilast is able to drive the altered profile of PsO-MSCs towards a more physiological pattern. In skin sections, the role of Apremilast is evident in reducing VEGF, iNOS and IDO expression.

Conclusion

Apremilast treatment influences the expression of VEGF, iNOS and IDO not only by keratinocytes but also by MSCs, restoring their intrinsic profile and their natural anti-inflammatory action, and decreasing the auto-inflammatory process that underpins the development of psoriasis.
Literature
1.
go back to reference Quaglino P, Bergallo M, Ponti R, et al. Th1, Th2, Th17 and regulatory T cell pattern in psoriatic patients: modulation of cytokines and gene targets induced by etanercept treatment and correlation with clinical response. Dermatology. 2011;223:57–67.CrossRef Quaglino P, Bergallo M, Ponti R, et al. Th1, Th2, Th17 and regulatory T cell pattern in psoriatic patients: modulation of cytokines and gene targets induced by etanercept treatment and correlation with clinical response. Dermatology. 2011;223:57–67.CrossRef
2.
go back to reference Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130:1785–2196.CrossRef Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130:1785–2196.CrossRef
3.
go back to reference Llamas-Velasco M, Bonay P, José Concha-Garzón M, et al. Immune cells from patients with psoriasis are defective in inducing indoleamine 2,3-dioxygenaseexpression in response to inflammatory. Br J Dermatol. 2017;176:695–704.CrossRef Llamas-Velasco M, Bonay P, José Concha-Garzón M, et al. Immune cells from patients with psoriasis are defective in inducing indoleamine 2,3-dioxygenaseexpression in response to inflammatory. Br J Dermatol. 2017;176:695–704.CrossRef
4.
go back to reference Sheipouri D, Grant R, Bustamante S, et al. Characterisation of the kynurenine pathway in skin-derived fibroblasts and keratinocytes. J Cell Biochem. 2015;116:903–22.CrossRef Sheipouri D, Grant R, Bustamante S, et al. Characterisation of the kynurenine pathway in skin-derived fibroblasts and keratinocytes. J Cell Biochem. 2015;116:903–22.CrossRef
5.
go back to reference Asp L, Johansson AS, Mann A, et al. Effects of pro-inflammatory cytokines on expression of kynurenine pathway enzymes in human dermal fibroblasts. J Inflamm. 2011;8:25.CrossRef Asp L, Johansson AS, Mann A, et al. Effects of pro-inflammatory cytokines on expression of kynurenine pathway enzymes in human dermal fibroblasts. J Inflamm. 2011;8:25.CrossRef
6.
go back to reference Campanati A, Orciani M, Sorgentoni G, et al. Indirect co-cultures of healthy mesenchymal stem cells restore the physiological phenotypical profile of psoriatic mesenchymal stem cells. Clin Exp Immunol. 2018a;193:234–40.CrossRef Campanati A, Orciani M, Sorgentoni G, et al. Indirect co-cultures of healthy mesenchymal stem cells restore the physiological phenotypical profile of psoriatic mesenchymal stem cells. Clin Exp Immunol. 2018a;193:234–40.CrossRef
7.
go back to reference Campanati A, Orcian M, Consales V, et al. Characterization and profiling of immunomodulatory genes in resident mesenchymal stem cells reflect the Th1-Th17/Th2 imbalance of psoriasis. Arch Dermatol Res. 2014;306:915–20.CrossRef Campanati A, Orcian M, Consales V, et al. Characterization and profiling of immunomodulatory genes in resident mesenchymal stem cells reflect the Th1-Th17/Th2 imbalance of psoriasis. Arch Dermatol Res. 2014;306:915–20.CrossRef
8.
go back to reference Orciani M, Campanati A, Salvolini E, et al. The mesenchymal stem cell profile in psoriasis. Br J Dermatol. 2011;165:585–92.CrossRef Orciani M, Campanati A, Salvolini E, et al. The mesenchymal stem cell profile in psoriasis. Br J Dermatol. 2011;165:585–92.CrossRef
9.
go back to reference Campanati A, Orciani M, Lazzarini R, et al. TNF-α inhibitors reduce the pathological Th(1)-Th(17)/Th(2) imbalance in cutaneous mesenchymal stem cells of psoriasis patients. Exp Dermatol. 2017;26:319–24.CrossRef Campanati A, Orciani M, Lazzarini R, et al. TNF-α inhibitors reduce the pathological Th(1)-Th(17)/Th(2) imbalance in cutaneous mesenchymal stem cells of psoriasis patients. Exp Dermatol. 2017;26:319–24.CrossRef
10.
go back to reference Campanati A, Orciani M, Gorbi S, et al. Effect of biologic therapies targeting tumour necrosis factor-α on cutaneous mesenchymal stem cells in psoriasis. Br J Dermatol. 2012;167:68–76.CrossRef Campanati A, Orciani M, Gorbi S, et al. Effect of biologic therapies targeting tumour necrosis factor-α on cutaneous mesenchymal stem cells in psoriasis. Br J Dermatol. 2012;167:68–76.CrossRef
11.
go back to reference Schett G, Sloan VS, Stevens RM, et al. Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis. 2010;2:271–8.CrossRef Schett G, Sloan VS, Stevens RM, et al. Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis. 2010;2:271–8.CrossRef
12.
go back to reference Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008;24:1529–38.CrossRef Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008;24:1529–38.CrossRef
13.
go back to reference Pincelli C, Schafer PH, French LE, Augustin M, Krueger JG. Mechanisms underlying the clinical effects of apremilast for psoriasis. J Drugs Dermatol. 2018;17(8):835–40.PubMed Pincelli C, Schafer PH, French LE, Augustin M, Krueger JG. Mechanisms underlying the clinical effects of apremilast for psoriasis. J Drugs Dermatol. 2018;17(8):835–40.PubMed
14.
go back to reference Campanati A, Orciani M, Sorgentoni G, et al. Pathogenetic characteristics of mesenchymal stem cells in hidradenitis suppurativa. JAMA Dermatol. 2018b;154:1184–90.CrossRef Campanati A, Orciani M, Sorgentoni G, et al. Pathogenetic characteristics of mesenchymal stem cells in hidradenitis suppurativa. JAMA Dermatol. 2018b;154:1184–90.CrossRef
15.
go back to reference Orciani M, Campanati A, Caffarini M, et al. T helper (Th)1, Th17 and Th2 imbalance in mesenchymal stem cells of adult patients with atopic dermatitis: at the origin of the problem. Br J Dermatol. 2017;176:1569–76.CrossRef Orciani M, Campanati A, Caffarini M, et al. T helper (Th)1, Th17 and Th2 imbalance in mesenchymal stem cells of adult patients with atopic dermatitis: at the origin of the problem. Br J Dermatol. 2017;176:1569–76.CrossRef
16.
go back to reference Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.CrossRef Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.CrossRef
17.
go back to reference Campanati A, Orciani M, Ganzetti G, et al. The effect of etanercept on vascular endothelial growth factor production by cutaneous mesenchymal stem cells from patients with psoriasis. J Int Med Res. 2016;44:6–9.CrossRef Campanati A, Orciani M, Ganzetti G, et al. The effect of etanercept on vascular endothelial growth factor production by cutaneous mesenchymal stem cells from patients with psoriasis. J Int Med Res. 2016;44:6–9.CrossRef
18.
go back to reference Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159:842–55.CrossRef Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159:842–55.CrossRef
19.
go back to reference Heidenreich R, Röcken M, Ghoreschi K. Angiogenesis drives psoriasis pathogenesis. Int J Exp Pathol. 2009;90:232–48.CrossRef Heidenreich R, Röcken M, Ghoreschi K. Angiogenesis drives psoriasis pathogenesis. Int J Exp Pathol. 2009;90:232–48.CrossRef
20.
21.
go back to reference Simonetti O, Lucarini G, Campanati A, et al. VEGF, survivin and NOS overexpression in psoriatic skin: critical role of nitric oxide synthases. J Dermatol Sci. 2009;54:205–8.CrossRef Simonetti O, Lucarini G, Campanati A, et al. VEGF, survivin and NOS overexpression in psoriatic skin: critical role of nitric oxide synthases. J Dermatol Sci. 2009;54:205–8.CrossRef
22.
go back to reference Cals-Grierson MM, Ormerod AD. Nitric oxide function in the skin. Nitric Oxide. 2004;10:179–93.CrossRef Cals-Grierson MM, Ormerod AD. Nitric oxide function in the skin. Nitric Oxide. 2004;10:179–93.CrossRef
23.
go back to reference Kroll J, Waltenberger J. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun. 1998;252:743–6.CrossRef Kroll J, Waltenberger J. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun. 1998;252:743–6.CrossRef
24.
go back to reference Merighi S, Gessi S, Varani K, et al. Hydrogen sulfide modulates the release of nitric oxide and VEGF in human keratinocytes. Pharmacol Res. 2012;66:428–36.CrossRef Merighi S, Gessi S, Varani K, et al. Hydrogen sulfide modulates the release of nitric oxide and VEGF in human keratinocytes. Pharmacol Res. 2012;66:428–36.CrossRef
25.
go back to reference Ito M, Ogawa K, Takeuchi K, et al. Gene expression of enzymes for tryptophan degradation pathway is upregulated in the skin lesions of patients with atopic dermatitis or psoriasis. J Dermatol Sci. 2004;36:157–64.CrossRef Ito M, Ogawa K, Takeuchi K, et al. Gene expression of enzymes for tryptophan degradation pathway is upregulated in the skin lesions of patients with atopic dermatitis or psoriasis. J Dermatol Sci. 2004;36:157–64.CrossRef
26.
go back to reference Criado G, Simelyte E, Inglis JJ, et al. Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/ Th17 cells in the joint in collagen-induced arthritis. Arthritis Rheum. 2009;60:1342–51.CrossRef Criado G, Simelyte E, Inglis JJ, et al. Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/ Th17 cells in the joint in collagen-induced arthritis. Arthritis Rheum. 2009;60:1342–51.CrossRef
27.
go back to reference Mancuso R, Hernis A, Agostini S, et al. Indoleamine 2,3 dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis. PLoS ONE. 2015;10:e0130715.CrossRef Mancuso R, Hernis A, Agostini S, et al. Indoleamine 2,3 dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis. PLoS ONE. 2015;10:e0130715.CrossRef
28.
go back to reference Trabanelli S. Indoleamine 2,3-dioxygenase in psoriasis: a defective mechanism. Br J Dermatol. 2017;176:570–2.CrossRef Trabanelli S. Indoleamine 2,3-dioxygenase in psoriasis: a defective mechanism. Br J Dermatol. 2017;176:570–2.CrossRef
29.
go back to reference Ribatti D, Nico B, Crivellato E. The role of pericytes in angiogenesis. Int J Dev Biol. 2011;55:261–8.CrossRef Ribatti D, Nico B, Crivellato E. The role of pericytes in angiogenesis. Int J Dev Biol. 2011;55:261–8.CrossRef
30.
go back to reference Covas DT, Panepucci RA, Fonte AM, et al. Mesenchymal stem cells, fibroblasts and pericytes: different functional states of the same cell? Blood. 2005;106:4310.CrossRef Covas DT, Panepucci RA, Fonte AM, et al. Mesenchymal stem cells, fibroblasts and pericytes: different functional states of the same cell? Blood. 2005;106:4310.CrossRef
31.
go back to reference Stapor PC, Sweat RS, Dashti DC, et al. Pericyte dynamics during angiogenesis: new insights from new identities. J Vasc Res. 2014;51:163–74.CrossRef Stapor PC, Sweat RS, Dashti DC, et al. Pericyte dynamics during angiogenesis: new insights from new identities. J Vasc Res. 2014;51:163–74.CrossRef
32.
go back to reference Shin TH, Kim HS, Choi SW, et al. Mesenchymal stem cell therapy for inflammatory skin diseases: clinical potential and mode of action. Int J Mol Sci. 2017;18(2):244.CrossRef Shin TH, Kim HS, Choi SW, et al. Mesenchymal stem cell therapy for inflammatory skin diseases: clinical potential and mode of action. Int J Mol Sci. 2017;18(2):244.CrossRef
Metadata
Title
The efficacy of in vivo administration of Apremilast on mesenchymal stem cells derived from psoriatic patients
Authors
Anna Campanati
Miriam Caffarini
Federico Diotallevi
Giulia Radi
Guendalina Lucarini
Mariangela Di Vincenzo
Monia Orciani
Annamaria Offidani
Publication date
01-01-2021
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 1/2021
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-020-01412-3

Other articles of this Issue 1/2021

Inflammation Research 1/2021 Go to the issue