TNF‐α inhibitors reduce the pathological Th₁–Th₁₇/Th₂ imbalance in cutaneous mesenchymal stem cells of psoriasis patients

Abstract

Psoriasis is a disease characterized by an imbalance between Th and Th and Th inflammatory axes, in which cutaneous mesenchymal stem cells (MSCs) are early involved, as they show a greater relative expression of several genes encoding for Th and Th cytokines. Therapeutic implications of TNF-α inhibitors on differentiated skin cells have been largely described in psoriasis; however, their effects on MSCs derived from patients with psoriasis have been only partially described. The aim of this work was to evaluate the effect of TNF-α inhibitors on cytokine milieu expressed by MSCs isolated from the skin of patients with psoriasis. Resident MSCs from skin of patients with psoriasis and healthy subjects have been isolated, characterized and profiled by PCR and ELISA for the expression of 22 cytokines involved in Th , Th and Th pathways, both before and after 12 weeks therapy with TNF-α inhibitors. The administration of TNF-α inhibitors for 12-weeks acts on MSCs as follows: it reduces the expression of several Th -Th cytokines whose levels are elevated at baseline (IL-6, IL-8, IL-12, IL-23A, IFN-γ, TNF-α, CCL2, CCL20, CXCL2, CXCL5, IL-17A, IL-17C, IL-17F, IL-21, G-CSF). Similarly, it enhances the expression of several Th cytokines which are underexpressed at baseline (IL-2, IL-4, IL-5), reducing the expression of those overexpressed at baseline (TGF-β and IL-13). TNF-α inhibitors could contribute to reduce the pathological imbalance between the Th -Th vs Th axis in MSCs of patients with psoriasis.

Indirect co-cultures of healthy mesenchymal stem cells restore the physiological phenotypical profile of psoriatic mesenchymal stem cells

“…The level of secreted cytokines at baseline confirm the imbalance of Th1/17 versus the Th2 axis also observed in our previous studies [4,8,23]: MSCs from psoriatic patients secrete higher amounts of Th1/Th17 inflammatory molecules (IL-6, IL-12, IL-13, IL-17A, TGF-b, IFN-g, TNF-a and G-CSF) than MSCs from control subjects. Conversely, IL-2 is less secreted by PsO-MSCs than H-MSCs.…”

“…It is now considered as one of the most common immune-mediated disorders, with an imbalance between T helper type 1 (Th1)/Th17 and Th2 cytokine expression [2]. MSCs isolated from skin of psoriatic patients show an imbalance between Th1/Th17 and Th2 pathways, reflecting the phenotype of differentiated skin cells [4,8]. In addition, the inflammatory process is maintained via a positive feedback loop due to the immune cell and cytokine production by keratinocytes [3][4][5][6][7].…”

“…In this scenario, it has been already demonstrated that mesenchymal stem cells (MSCs) are involved early in psoriasis onset and progression. MSCs isolated from skin of psoriatic patients show an imbalance between Th1/Th17 and Th2 pathways, reflecting the phenotype of differentiated skin cells [4,8]. Even more, an altered microenvironment in psoriatic lesions may induce resident MSCs to produce angiogenic and proinflammatory mediators sustaining skin lesion development [9].…”

Psoriasis – What′s Up ?

“…in a thoughtful commentary . Based on the central role of TNFα, Campanati et al . demonstrate profound effects of TNF inhibition on numerous components of the cytokine network, while Balato et al .…”

“…[5] Neutrophilic granulocytes have been "rediscovered" recently as prominent players in this and other pathogenic processes in psoriasis, a notion that is highlighted in a viewpoint article and a corresponding commentary. [6,7] Further evincing the pivotal role of the cytokine network in [8,9] Based on the central role of TNFα, Campanati et al [10] demonstrate profound effects of TNF inhibition on numerous components of the cytokine network, while Balato et al [11] highlight its influence on mTOR regulation. With new therapies in mind, Mykicki et al [12] show that the KdPT tripeptide, a novel αMSH analogue, can also skew the cytokine balance in psoriasis.…”