Activation of Discoidin Domain Receptor 1 Facilitates the Maturation of Human Monocyte-Derived Dendritic Cells Through the TNF Receptor Associated Factor 6/TGF-β-Activated Protein Kinase 1 Binding Protein 1β/p38α Mitogen-Activated Protein Kinase Signaling Cascade

Abstract

Maturation of dendritic cells (DCs) is critical for their ability to stimulate resting naive T cells in primary immune responses. Previous studies demonstrated that collagen, such as type I collagen, could facilitate DC maturation; however, the basis of collagen-mediated DC maturation remains unclear. Discoidin domain receptor 1 (DDR1) is a nonintegrin collagen receptor constitutively expressed in a variety of epithelial cells, including tumor cells, and is inducible in leukocytes. In this study, we evaluated the role of DDR1 in DC maturation using human monocyte-derived DCs. Two DDR1 isoforms, DDR1a and DDR1b, were expressed in both immature and mature DCs. Activation of DDR1 on immature DCs resulted in their partial maturation; however, DDR1 activation markedly amplified TNF-α- and LPS-induced phenotypic and functional maturation of DCs through activation of p38 mitogen-activated protein kinase (MAPK), suggesting the involvement of DDR1b in this process. Activation of DDR1b on differentiated DDR1b-overexpressing THP-1 cells or DDR1 on mature DCs induced the formation of TNFR associated factor 6 (TRAF6)/TGF-β-activated kinase 1 binding protein 1β/p38α MAPK complex and p38α autophosphorylation. Transfection of differentiated DDR1b-overexpressing THP-1 cells with dominant negative TRAF6 completely abrogated DDR1b-mediated p38 MAPK phosphorylation, indicating a critical role of TRAF6 in DDR1b-mediated p38 MAPK activation. Taken together, our data suggest that DDR1b-collagen interaction augments the maturation of DCs in a tissue microenvironment through a unique TRAF6/TGF-β-activated kinase 1 binding protein 1β/p38α MAPK signaling cascade and contributes to the development of adaptive immune responses.

Activation and signaling of the p38 MAP kinase pathway

“…Although there is an indication that TAB1-dependent p38 phosphorylation occurs in LPS, TNF, and CpG treated B cell lines, a study using MKK3/6 knockout MEF cells showed that TNFinduced p38 activation is solely dependent on MKKs [29]. While the biological contexts of MKK-independent p38 activation still need further investigation, there is a couple of recent publications that support the role TAB-dependent p38 activation under physiological conditions [30][31][32]. This suggests that the activation mechanisms of p38 may vary in different cells under various physiological or pathological conditions.…”

Collagens in the progression and complications of atherosclerosis

“…71 DDR1 expression was also detected in vivo on leukocytes invading renal carcinomas. 71 The receptor regulates several macrophage functions important in inflammation, including the maturation and antigen presentation function of human monocyte-derived dendritic cells, 72 and nitric oxide production. 73 Two splice variants of DDR1 are expressed in PBMCs, DDR1a and DDR1b, and they mediate different responses.…”

Activation of Discoidin Domain Receptor 1 Isoform b with Collagen Up-Regulates Chemokine Production in Human Macrophages: Role of p38 Mitogen-Activated Protein Kinase and NF-κB

“…We further identified that activation of DDR1b induces the formation of a protein complex containing TNFR-associated factor 6 (TRAF6), TGF-␤-activated protein kinase 1 (TAK1)-binding protein 1␤ (TAB1␤), and p38␣ MAPK, and subsequent autophosphorylation of p38␣ MAPK in PMA-treated THP-1 cells (14), indicating that the DDR1b signaling targets the p38 MAPK pathway through an alternative mechanism for p38 MAPK activation in these cells (15,16). We confirmed our data with PMA-treated THP-1 cells using GM-CSF-induced, human monocyte-derived primary macrophages (GM macrophages) (13,14). It is well known that TRAF6 mediates the signaling of other receptors, including IL-1R, Tolllike receptors (TLRs) TRANCE-R, and CD40 (17,18).…”