Contribution of fibroblast-MMP14 to allergic-type of contact dermatitis reactions

• Applicant: Paola Zigrino, Ph.D.
• Subject Area: Dermatology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516569227

Local degradation of connective tissue by matrix metalloproteinases (MMPs) is essential in maintaining skin homeostasis during tissue repair and remodelling. While MMPs are produced at low levels in normal skin, expression is rapidly induced in response to different environmental stimuli, including cytokines, growth factors, and by the interaction of cells with extracellular matrix proteins. MMPs are zinc-dependent endopeptidases with common functional domains, activation mechanisms, and the ability to remodel the extracellular matrix (ECM). The structural and functional properties of the ECM can modulate multiple processes, including morphogenesis and inflammatory responses, such as the migration of immune cells within inflamed tissue, their activation, proliferation, and polarization. Among the various cells populating the skin, tissue-resident fibroblasts produce many pro- and anti-inflammatory factors, ECM molecules, and MMPs that contribute to physiological and pathological skin conditions. In vivo deletion of MMP-14 in fibroblasts demonstrated the primary role of this collagenase in maintaining skin homeostasis. Further investigations using this mouse model of MMP-14 fibroblasts-specific deletion showed that this cell source of the protease regulates inflammatory immune responses in a context-specific manner. In fibroblasts, the absence of MMP-14 alters allergic contact dermatitis (ACD) but not irritant dermatitis, suggesting a specific role in different inflammatory reactions of the skin. In ACD, the deletion of MMP-14 in fibroblasts explicitly promotes CD8 but not CD4 cells, leads to increased expression of various growth factors and cytokines, and may cause keratinocyte proliferation. The molecular mechanisms underlying the regulation of ACD by fibroblast MMP-14 are still unknown and will be analyzed in this project. Based on our previous findings we will (1) characterize ACD reaction and (2) define cell-Intrinsic and extrinsic mechanisms of action of MMP-14 during these reactions. Our results will provide new insights into fibroblast MMP-14 in the pathogenesis of allergic contact dermatitis and the interaction between the stroma and the immune system. Translationally, our findings may allow the development of new specific strategies for preventing and treating ACD and other related skin diseases.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Mario Fabri