Cellular and molecular mechanisms of TNF (tumor necrosis factor-alpha) mediated protection in atopic dermatitis
Final Report Abstract
A variety of novel aspects relevant to immunology, inflammation, skin homeostasis and deviation from the same were revealed in this project. In detail, we provided insights into novel aspects of the network behind atopic dermatitis (AD) development and aggravation. Since AD patients are reportedly characterized by decreased TNF expression, and eczema outburst is a possible side-effect of TNF-directed therapies, we have illuminated the mechanisms by which TNF counteracts AD and have clarified why TNF neutralization (a common treatment in autoimmune disorders) can lead to the eruption of eczema. Mechanistically, we have identified elements underlying the inter-relationships between mast cells (MCs) and keratinocytes (KCs), and several constituents involved in their cross-regulation and cross-activation. In particular, MC products possess TSLP-promoting activity and tryptase is vital in this scenario; this connection seems to apply to murine and human skin alike. TSLP, in its own right, controls MC survival, creating MC hyperplasia and thus a positive feed-forward loop. Based on these findings we predict that therapeutic interference with pathological MC increase, with MC function or with specific MC mediators (especially tryptase) will be able to facilitate AD amelioration, especially in those patient endotypes or subgroups characterized by evident deregulations in their lesional MC compartments. Regarding TSLP, on the other hand, it is notable that TSLP targeting is currently being evaluated in clinical trials for asthma and atopic dermatitis. In summary, the enhanced AD in TNF-deficient surroundings depends on TSLP and MCs, and both of these factors are extensively inter-connected. We identified a feed forward activating loop between lacking TNF -> MCs -> tryptase -> TSLP -> MCs (further strengthened) -> tryptase -> more TSLP and so on and so forth, i.e. a dynamic vicious-cycle.
Publications
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(2020) Thymic stromal lymphopoietin production induced by skin irritation results from concomitant activation of protease-activated receptor 2 and interleukin 1 pathways. The British journal of dermatology 182 (1) 119–129
Redhu D, Franke K, Kumari V, Babina M, Worm M.
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Thymic stromal lymphopoietin induction by skin irritation is independent of tumour necrosis factor-α but supported by interleukin-1. Br J Dermatol. 2015 Apr;172(4):951-60
Kumari V, Babina M, Hazzan T, Worm M
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An efficient method for gene knock-down by RNA interference in human skin mast cells. Exp Dermatol. 2017 Nov;26(11):1136-1139
Hazzan T, Guhl S, Artuc M, Franke K, Worm M, Zuberbier T, Babina M
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Apoptotic resistance of human skin mast cells is mediated by Mcl-1. Cell Death Discov. 2017b Aug 21;3:17048
Hazzan T, Eberle J, Worm M, Babina M
