Abstract

Epidermal Langerhans cells (LCs) are skin-resident dendritic cells that are essential for the induction of skin immunity and tolerance. Transforming growth factor-β 1 (TGFβ1) is a crucial factor for LC maintenance and function. However, the underlying TGFβ1 signaling pathways remain unclear. Our previous research has shown that the TGFβ1/Smad3 signaling pathway does not impact LC homeostasis and maturation. In this study, we generated mice with conditional deletions of either individual Smad2, Smad4, or both Smad2 and Smad4 in the LC lineage or myeloid lineage, to further explore the impact of TGFβ1/Smad signaling pathways on LCs. We found that interruption of Smad2 or Smad4 individually or simultaneously in the LC lineage did not significantly impact the maintenance, maturation, antigen uptake, and migration of LCs in vivo or in vitro during steady state. However, the interruption of both Smad2 and Smad4 pathways in the myeloid lineage led to a dramatic inhibition of bone marrow-derived LCs in the inflammatory state. Overall, our data suggest that canonical TGFβ1/Smad2/4 signaling pathways are dispensable for epidermal LC homeostasis and maturation at steady state, but are critical for the long-term LC repopulation directly originating from the bone marrow in the inflammatory state.

Highlights

  • Epidermal Langerhans cells (LCs) functionally serve as a unique subset of skin-resident dendritic cells (DCs), they are classified as a specialized macrophage subset in skin based on their developmental relationship like tissue resident macrophage derived from embryonic precursors [1]

  • We previously reported that TGFβR/Smad3 signaling pathway was inessential for LC development [16]

  • Expression of Smad2 in epidermal LCs from Human LangerinCre (hLanCre) Smad2fl/fl mice was dramatically reduced compared to wild type (WT) littermates; this was confirmed by quantitative RT-PCR (Figure 1A)

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Summary

Introduction

Epidermal Langerhans cells (LCs) functionally serve as a unique subset of skin-resident dendritic cells (DCs), they are classified as a specialized macrophage subset in skin based on their developmental relationship like tissue resident macrophage derived from embryonic precursors [1]. LCs represent the first antigen-presenting cells in the skin that encounter foreign. LCs phagocytize epidermal detritus with their dendritic protrusions and eventually present these antigens on the cell surface with an MHCII molecule [6]. Following cell activation by various stimuli, LCs have increased expression of costimulatory markers CD80 and CD86, decreased expression of epithelial cell adhesion molecule (EpCAM) and E-cadherin, and acquire a migratory phenotype. These changes result in LC migration to the regional draining lymph nodes (LNs), where the LCs interact with naïve T cells to induce immunity or tolerance [3, 7]. The specific underlying mechanisms that precisely regulate LC development and function are still not fully understood

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