The Axl/Gas6 phagocytosis receptor system is constitutively upregulated by Langerhans cells in response to epidermal TGF-β1. (147.15)

Abstract

Abstract Tyro-3, Axl and Mer (TAM) receptor tyrosine kinases represent an anti-inflammatory phagocytosis system, which is upregulated on myeloid cells by interferon-α during inflammation. These receptors use their ligands protein S and Gas6 for recognizing phosphatidylserine on apoptotic cells. Activation leads to a block in pro-inflammatory cytokine production, therefore implicating this system in silent phagocytosis and resolution of inflammation. We here identified Axl to be induced by TGF-β1 during Langerhans cell commitment of human CD34+ myeloid progenitor cells and monocytes. Axl surface expression was specific for LCs, since it could not be detected in other myeloid DC subsets and macrophages. We further demonstrate that Axl and Gas6 are upregulated in human skin in vivo; strong induction was seen in the suprabasal keratinocyte layers, thereby co-localized with TGF-β1. Vitamin K activates TAM ligands; accordingly VK addition promoted in vitro LC differentiation and enhanced E-cadherin expression; conversely antibody inhibition of Axl showed an inverse effect. TAM KO mice exhibited reduced LC numbers, and this effect preceded the development of lupus like disease and associated skin inflammation previously identified in these mice. Therefore, TGF-β1 controls the steady-state expression of Axl in DCs. Constitutive Axl expression by epidermal LCs may play a key role during silent phagocytosis and resolution of inflammation, previously known to be largely dependent on TGF-β.