The skin is the largest organ of our body — in terms of both weight and surface area. One of its many functions is to provide a protective barrier between the external and internal environment. However, it is more than a physical barrier: it is an active immune organ.
Skin defenses are organized around a complex regulatory network that includes not only cellular, but also microbial components. Indeed, the skin is an ecosystem composed of diverse habitats — folds, invaginations and specialized niches that support a large variety of microorganisms, the skin microbiota. The skin is also home to different cell types. While cells such as macrophages, dendritic cells and mast cells have long been recognized as members of the skin defense network, recent independent breakthroughs reveal the participation of other cell types — notably memory T lymphocytes and adipocytes.
Recently, results from a study carried out by a team of scientist at the Brigham and Women’s Hospital in Boston demonstrated that the human skin is protected by four functionally distinct types of memory T cells, which include two populations of resident T cells and two populations of recirculating T cells. Although the presence in mouse and human skin of both resident and recirculating memory T cells was already known, this recent study advances our understanding of skin defenses by providing novel information on the physical distribution of the four distinct subpopulations, their relative proportions and their functional activities. Each subpopulation is likely to play a unique role in protecting against infectious pathogens — and not only. Both resident and recirculating memory T cells are known to contribute to human diseases of the skin. For example, psoriasis is linked to dysregulated resident memory T cells, whereas leukemic variants of cutaneous T cell lymphoma represent a malignancy of the recirculating cells.
The discovery of different subpopulations of resident and recirculating memory T cells highlights the complexity of the skin defense network. Such complexity is augmented by the contribution of a cell type that, until recently, was not a known member of the network: the adipocyte. Adipocytes are cells specialized in storing energy as fat — in other words, they’re the so-called fat cells.
The skin consists of two layers – the outermost epidermis, and the underlying dermis. Beneath the dermis lies the subcutaneous adipose tissue, which is mostly made up of adipocytes. Not too long ago, Richard Gallo and collaborators noticed that infections by methicillin-resistant Staphylococcus aureus (MRSA) resulted in a considerable enlargement of the mouse dermal adipose tissue as a consequence of an increase in both size and number of adipocytes.
They found that two adipogenesis-inducing transcription factors, zinc finger protein 423 (ZFP423) and peroxisome proliferator–activated receptor γ (PPARγ), mediated the increase in adipose tissue. Inhibition of these transcription factors, and therefore inhibition of adipogenesis (the process by which pre-adipocytes differentiate to adipocytes), resulted in increased severity of skin infection, indicating a possible adipocyte role in promoting host defense against MRSA.
How do adipocytes, then, participate in host defense? The researchers discovered that differentiating adipocytes — in response to infection — secrete cathelicidin, which can directly kill bacteria. Cathelicidin is an antimicrobial peptide produced mostly by macrophages and neutrophils — the ability of adipocytes to secrete antimicrobial peptides came as a surprise. Interestingly, mature adipocytes produced less cathelicidin. Cathelicidin-deficient mice exhibited increased bacterial growth, whereas inhibition of adipogenesis in these mice did not result in a more severe infection. Thus, cathelicidin is the main player in the host defense mediated by adipocytes.
How can these recent discoveries guide development of novel therapeutic approaches? At this point, we are in the realm of speculation. The characterization of memory T cells subpopulations at the level of phenotypic and functional properties could lead to their selective and differential targeting for autoimmune and inflammatory diseases of the skin. Indeed, the current therapeutic modalities for these disorders do not take into account the involvement of the relevant memory T cells. Similarly, it is reasonable to expect that the increased understanding of the skin memory T cell system will influence the development of novel vaccination strategies that induce, when needed, generation of the appropriate memory T cell subpopulations.
Could adipocytes be the target of therapeutic approaches designed to treat MRSA infections? Conditions that hinder pre-adipocyte functions can predispose to infection. Thus, one approach could be to restore these functions, even using adipocyte stem cell therapy. What about augmenting cathelicidin production by normal adipocytes during infection? Adipocytes express a variety of toll-like receptors (TLRs), and the sensing of S. aureus by adipocytes might be TLR-mediated, most likely by TLR2. Thus, it has been proposed that PPARγ agonists could be pharmacologically used to control cathelicidin production by targeting the TLR2-ZFP423-PPARγ -cathelicidin pathway. An additional potential therapeutic approach could be based on vitamin D. Indeed, 1,25-Dihydroxyvitamin D3, the active form of vitamin D, is a major regulator of cathelicidin expression in monocytes and in epidermal keratinocytes, and is also known to modulate adipocyte function. It could be worth to determine whether or not vitamin D regulates cathelicidin expression in adipocytes, and explore the possibility of using vitamin D to support the current therapeutic modalities for MRSA infections.
These proposed approaches seem logical. However, in the airways, S. aureus exploits cathelicidin to promote staphylokinase-dependent fibrinolysis, leading to enhanced bacterial dissemination and invasive infection. Although the same pathogenic mechanism may not be operating in the skin, development of the proposed therapeutic approaches will need to take into account the potential unwanted interaction of S. aureus with cathelicidin.
The exciting discovery of unexpected players that may contribute to protective responses will guide, in the next few years, the design of novel therapeutic strategies that selectively target specific cell types — to effectively control infections and autoimmune/inflammatory diseases of the skin.