Abstract
In the protective responses of epithelial tissues, not only immune cells but also non-immune cells directly respond to external agents. Epithelial cells can be involved in the organization of immune responses through two phases. First, the exogenous harmful agents trigger the primary responses of the epithelial cells leading to various types of immune cell activation. Second, cytokines produced by the immune cells that are activated directly by the external agents and indirectly by the epithelial cell products elicit the secondary responses giving rise to further propagation of immune responses. TRAF6 is a ubiquitin E3 ligase, which intermediates between various types of receptors for exogenous agents or endogenous mediators and activation of subsequent transcriptional responses via NF-kappaB and MAPK pathways. TRAF6 ubiquitously participates in many protective responses in immune and non-immune cells. Particularly, epithelial TRAF6 has an essential role in the primary and secondary responses via driving type 17 response in psoriatic inflammation of the skin. Consistently, many psoriasis susceptibility genes encode the TRAF6 signaling players, such as ACT1 (TRAF3IP2), A20 (TNFAIP3), ABIN1 (TNIP1), IL-36Ra (IL36RN), IkappaBzeta (NFKBIZ), and CARD14. Herein, we describe the principal functions of TRAF6, especially in terms of positive and regulatory immune controls by interaction between immune cells and epithelial cells. In addition, we discuss how TRAF6 in the epithelial cells can organize the differentiation of immune responses and drive inflammatory loops in the epithelial immune microenvironment, which is termed EIME.
Highlights
The epithelial tissues compose the outermost surface of an organism
We have demonstrated that tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) in the epithelial keratinocytes is essential for driving interleukin (IL)-17mediated psoriatic inflammation [3]
T cell receptor (TCR) and B cell receptor (BCR) pathways signal via CARD11/CARDcontaining MAGUK protein 1 (CARMA1) while C-type lectin receptor (CLR) pathways signal via CARD9 (Figure 2D)
Summary
The epithelial tissues compose the outermost surface of an organism. Epithelial cells are the first line confronting the exogenous harmful factors, such as toxins and infectious agents. The roles of signaling pathways of epithelial cells in the decision of the type of immune responses and their propagation have not been fully understood. The TRAF6 signaling pathways in the epithelial tissues are expected to play a pivotal role in IL-17-mediated inflammatory and protective responses. Binding K63-linked polyubiquitin chains to the target molecules plays a crucial role in a variety of immunological functions via regulating intracellular signal transduction [8,9,10]. Assays in vitro demonstrated that TRAF6 is crucial in IL-1 and CD40 signaling and in lipopolysaccharide (LPS) signaling [13] These findings established unexpectedly diverse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, innate immune responses, and cytokine signaling. Further investigation using conditional gene knockout techniques has clarified the immunological phenotypes of TRAF6 deficiency in each immune and epithelial cell subset (described and discussed in chapters 4 and 5, respectively)
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