The skin forms our outermost barrier to pathogens, water loss, mechanical or chemical insults, but is also home to a range of commensals. The skin immune system has to distinguish harmless foreign and self-antigens from pathogen-derived antigens to induce appropriate tolerance or protective immune responses. Intact skin immunity is essential for host defence, whereas deregulated immune responses can cause inflammatory skin diseases.
Shedding light into the interplay between resident immunocytes and the surrounding tissue will help to better understand pathomechanisms related to inflammation, autoimmunity, cancer, or graft-versus-host disease, and potentially to refine immunotherapies. Results from this project will also help identify basic principles of tissue homeostasis as well as pathophysiological mechanisms linked to disturbed cell polarity.
Moreover, findings obtained by studying mammalian skin might be relevant for the pathogenesis of other barrier-forming organs such as lung, kidney and intestine.
In invertebrates, polarity proteins have been demonstrated to couple cell shape to control of growth and differentiation. Ongoing efforts aim at dissecting the role of the apical Par3-atypical PKC-Par6 polarity complex in regulation of cellular asymmetry and fate.
We recently identified mammalian Par3 as a rheostat of epidermal homeostasis by controlling stem cell maintenance and keratinocyte differentiation (Ali et al., 2016). Moreover, our work unravelled underlying mechanochemical signalling networks, with Par3 coupling genome integrity and epidermal fate through shaping keratinocyte mechanics (Dias Gomes, Letzian et al., 2019). Dysregulation of polarity proteins is also a frequent event associated with tumor formation or progression (Mescher & Iden, 2015). In epidermal cancers, we found tumor-type dependent pro-oncongenic and tumor-suppressive functions of Par3 (Iden et al., 2012).
Furthermore, we demonstrated genetic interactions of Par3 and aPKCl in different stages of skin tumorigenesis, with Par3/aPKCl jointly fostering tumor-promoting inflammatory signals (Vorhagen, Kleefisch et al., 2018). Importantly, our work also revealed mechanistic insights into extrinsic roles of polarity regulators for melanocyte behaviour, melanoma formation and metastasis (Mescher, Jeong et al., 2017), underpinning the broad relevance and function of mammalian polarity proteins in tissue homeostasis and disease.