Research ArticleSKIN INFLAMMATION

A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury

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Science Immunology  23 Aug 2019:
Vol. 4, Issue 38, eaax8704
DOI: 10.1126/sciimmunol.aax8704

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Resurrecting sentinels in the skin

Langerhans cells are resident innate immune cells in the skin that play essential roles in promoting local immune responses and in maintaining skin homeostasis. Langerhans cells arise from fetal progenitors that seed the skin early in development. Here, Ferrer et al. have used a hematopoietic stem cell transplant model to examine the consequences of immune damage and loss of Langerhans cells in adult mouse skin. They report that monocytes from the blood infiltrate the skin and eventually replenish the Langerhans cell network, albeit the process by which monocytes give rise to Langerhans cells is not particularly efficient. Their findings are in agreement with studies reporting the ability of monocytes to replenish tissue-resident macrophages at other sites.

Abstract

A dense population of embryo-derived Langerhans cells (eLCs) is maintained within the sealed epidermis without contribution from circulating cells. When this network is perturbed by transient exposure to ultraviolet light, short-term LCs are temporarily reconstituted from an initial wave of monocytes but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this process is relevant to immunopathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where alloreactive T cells directly target eLCs, we have asked whether and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of long-term LCs in this context. Destruction of eLCs leads to recruitment of a wave of monocytes that engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LCs acquire the capacity of self-renewal, and proliferation in the epidermis matched that of steady-state eLCs. However, we identified a bottleneck in the differentiation and survival of epidermal monocytes, which, together with the slow rate of renewal of mature LCs, limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.

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