Defining the monocyte hair follicle niche: rebuilding the Langerhans cell network in skin

The skin is our primary physical and immune barrier to the outside world. With age, skin barrier function deteriorates, increasing susceptibility to infectious and non-infectious diseases and chronic wounds. Langerhans cells (LCs), specialised macrophages residing in the outer epidermis, are central to skin function. LC loss disrupts both immune and non-immune skin functions, and LC density declines with age. Understanding how the LC network is sustained throughout life is therefore essential for maintaining and enhancing skin barrier function. LCs are maintained through local self-renewal in the epidermis, but skin damage initiates repair by recruited blood-derived monocytes. Our previous work demonstrated that monocyte-derived (m)LCs can become long-lived, self-renewing cells that transcriptionally and functionally mirror the LCs they replace. This raises the key question: how does the skin anatomy enable short-lived monocytes to differentiate into long-lived LCs that are integrated in the keratinocyte layers of the epidermis? Our new findings have begun to address this question. We show that the hair follicle serves as both a critical entry point and site of fate determination for monocytes. Monocytes entering the upper hair follicle express epithelial cell adhesion molecule (EpCAM) and encounter its homotypic ligand on epithelial cells. EpCAM expression is associated with transition from a macrophage-like state to a LC-specific genetic programme. While EpCAM signalling pathways are well-defined in stem and cancer cell differentiation their role in immune cell fate remains unexplored. The junctional zone within the upper hair follicle is a recognised stem cell niche, supporting a pool of epidermal stem cells that migrate to repair the epidermis after skin wounding. We further propose that monocytes leverage these stem cell pathways to repopulate the basal epidermis with mLCs. This study aims to uncover the molecular and cellular mechanisms by which the hair follicle niche facilitates rebuilding of the LC network by monocytes after damage or wounding. We hypothesise that the loss of this niche contributes to the age-related decline in LC density and skin barrier function. To address this aim we will explore: How monocyte localisation at the upper hair follicle determines mLC identity, focusing on EpCAM signalling in monocyte fate specification. How monocytes migrate from the hair follicle to interfollicular regions, and how the junctional stem cell niche supports this process. By integrating immunology and stem cell biology, this research will advance our understanding of how skin anatomy supports monocyte differentiation to maintain the LC network. Understanding the spatial signals within the hair follicle that guide monocyte differentiation will shed light on immune cell integration in epithelia and how these processes fail in aged or diseased skin and more broadly at other epithelial barriers. This work aligns with BBSRC’s priority of promoting healthy aging. Chronic skin diseases and wounds impose a significant burden on the elderly, and improved knowledge of LC biology could inform strategies to sustain skin barrier function and enhance wound healing, reducing medical interventions. Furthermore, as a key site for vaccination, maintaining skin immune function is vital for human and animal health.