TNF-α counters skin inflammation by restraining mast cell-dependent thymic stromal lymphopoietin production

Background: TNF-a is an important proinflammatory cytokine, but its neutralization in the management of inflammatory skin disorders like psoriasis may trigger eczematous skin lesions as an adverse reaction. Objectives: This study aimed to elucidate whether TNF-a may protect from skin inflammation and to identify in detail the underlying mechanisms. Methods: Wild-type, TNF-a-deficient, thymic stromal lymphopoietin (TSLP) receptor-deficient, mast cell (MC)-deficient, TNF-a-TSLP receptor double-deficient, and TNF-a-MC double-deficient mice were subjected to a skin inflammation model and inspected by physical, clinical, histologic, immunohistochemical, and bioanalytic techniques. Results: TNF-a deficiency promoted skin inflammation. This was accompanied by MC hyperplasia and potent TSLP production in lesional skin and serum of TNF-a-deficient mice. Specifically, MCs were found to be responsible for inducing high levels of TSLP in the epidermis, compromising barrier function and initiating inflammation. In contrast, the production of immunoglobulins, including IgE, was reduced in mice lacking TNF-a. Conclusions: TNF-a restrains MC-dependent TSLP production and the onset of eczema. (J Allergy Clin Immunol 2025;156:150-8.)