Immune Control by TRAF6-Mediated Pathways of Epithelial Cells in the EIME (Epithelial Immune Microenvironment)

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.

Synergistic effect of Huyang Yangkun Formula and embryonic stem cells on 4-vinylcyclohexene diepoxide induced premature ovarian insufficiency in mice

“…In this study in mice, it was also significantly affected by VCD, and compared with the MOD group, combination therapy had a more significant effect than HYYKF or ESCs alone. The activation of TAK1 relies on its specific binding protein called TAB, as well as TRAF6 [ 33 – 36 ]. Among them, TAB1 mediates the autophosphorylation of TAK1, while TAB2 binds with TRAF6, inducing the activation of TAK1.…”

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“…TRAF6 is an E3 ligase involved in multiple immune signaling pathways, including those of RLRs, TLRs, IL-1 receptor, TGFβ receptors and B-cell receptors. Upon activation of these upstream receptors, TRAF6 is recruited to the receptors or downstream signaling complexes [95] , [96] , which triggers its E3 ligase activity to synthesize K63-Ub n . While the precise activation mechanism and ubiquitination target of TRAF6 has been unclear, the current model is that K63-Ub n conjugation within the signaling complex (either on TRAF6 or other targets) enables recruitment of various signaling molecules, leading to the activation of NF-kB, MAPK and/or IRF pathways [96] , [97] .…”

Microglia Contribution to the Regulation of the Retinal and Choroidal Vasculature in Age-Related Macular Degeneration

“…A few other studies suggested that inhibition of microglia-driven inflammation might be beneficial for the treatment of neovascular AMD, these included the knockdown of tumor necrosis factor receptor-associated factor 6 (TRAF6), the inhibition of sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC11) receptor and β2-adrenergic receptor. TRAF6 facilitates the inflammatory response in microglia and macrophages and promotes tumor angiogenesis via upregulating the expression of HIF-1a and VEGF [176]. Intravitreal administration of TFAF6 siRNA inhibits the activation of microglia and macrophages, the formation of CNV and the expression of HIF-1a and VEGF [177].…”