Pimecrolimus interferes the therapeutic efficacy of human mesenchymal stem cells in atopic dermatitis by regulating NFAT-COX2 signaling

Abstract

Background Human mesenchymal stem cells (hMSCs) therapy has recently been considered a promising treatment for atopic dermatitis (AD) due to their immunomodulation and tissue regeneration ability. In our previous studies, we demonstrated that hMSCs alleviate allergic inflammation in murine AD model by inhibiting the activation of mast cells and B cells. Also our phase I/IIa clinical trial showed clinical efficacy and safety of hMSCs in moderate-to-severe adult AD patients. However, hMSCs therapy against atopic dermatitis have had poor results in clinical field. Therefore, we investigated the reason behind this result. We hypothesized that drug–cell interaction could interfere with the therapeutic efficacy of stem cells, and investigated whether coadministration with pimecrolimus, one of the topical calcineurin inhibitors, could influence the therapeutic potential of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in AD. Methods hUCB-MSCs were subcutaneously injected to AD-induced mice with or without pimecrolimus topical application. To examine whether pimecrolimus influenced the immunomodulatory activity of hUCB-MSCs, hUCB-MSCs were treated with pimecrolimus. Results Pimecrolimus disturbed the therapeutic effect of hUCB-MSCs when they were co-administered in murine AD model. Moreover, the inhibitory functions of hUCB-MSCs against type 2 helper T (Th2) cell differentiation and mast cell activation were also deteriorated by pimecrolimus treatment. Interestingly, we found that pimecrolimus decreased the production of PGE2, one of the most critical immunomodulatory factors in hUCB-MSCs. And we demonstrated that pimecrolimus downregulated COX2-PGE2 axis by inhibiting nuclear translocation of NFAT3. Conclusions Coadministration of pimecrolimus with hMSCs could interfere with the therapeutic efficacy of hMSCs in atopic dermatitis, and this is the first study that figured out the interaction of hMSCs with other drugs in cell therapy of atopic dermatitis. Therefore, this study might give rise to improvement of the clinical application of hMSCs therapy and facilitate the widespread application of hMSCs in clinical field.

Therapeutic effects of mesenchymal stem cells and their derivatives in common skin inflammatory diseases: Atopic dermatitis and psoriasis

“…The first one is that subcutaneous administration of UCB-MSCs with 2 × 10 6 cells in mice can decrease the level of TNFα to inhibit the infiltration of mast cells and decrease the level of IgE into skin lesions by secreting TGF-β ( 18 ). Second is that subcutaneous administration of UCB-MSCs in mice (2 × 10 6 cells) can reduce allergic inflammatory symptoms by inhibiting Th2 cell differentiation and mast cell activation through the cyclooxygenase-2 (COX2)–prostaglandin E2 (PGE2) pathway ( 60 ). The last is that subcutaneous administration of UCB-MSCs in mice (2 × 10 6 cells) can decrease the level of pro-inflammatory cytokines including IL-4, TNF-α, thymus, activation-regulated chemokine (TARC), and IL-22 through secreting the epidermal growth factor (EGF) in skin lesion ( 61 ) ( Table 1 ).…”

Inhibition of Mast Cell Degranulation in Atopic Dermatitis by Celastrol through Suppressing MRGPRX2

“…Mast cells activated in atopic dermatitis release a large number of inflammatory cytokines, histamine, and protease through degranulation [ 7 , 8 ] and play an important role in regulating inflammatory response and itching [ 9 , 10 ]. Mas-related G protein-coupled receptor-X2 (MRGPRX2) is specifically expressed by skin mast cells and is considered a new marker for regulating mast cell degranulation, chronic inflammation, and anaphylaxis [ 11 ].…”

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“…Its use has successfully treated inflammatory skin conditions like vitiligo, seborrheic dermatitis, oral lichen planus, cutaneous lupus erythematosus, and psoriasis [8][9][10][11][12] . The calcineurin inhibitors pimecrolimus and tacrolimus have been approved by the USFDA for the treatment of skin conditions [13][14] .…”