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

Abstract

Macrophages produce an array of proinflammatory mediators at sites of inflammation and contribute to the development of inflammatory responses. Important roles for cytokines, such as IL-1 or TNF-α, and bacterial products, such as LPS, in this process have been well documented; however, the role for the extracellular matrix proteins, such as collagen, remains unclear. We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, is expressed during differentiation of human monocytes into macrophages, and the interaction of the DDR1b isoform with collagen facilitates their differentiation via the p38 mitogen-activated protein kinase (MAPK) pathway. In this study, we report that the interaction of DDR1b with collagen up-regulates the production of IL-8, macrophage inflammatory protein-1α, and monocyte chemoattractant protein-1 in human macrophages in a p38 MAPK- and NF-κB-dependent manner. p38 MAPK was critical for DDR1b-mediated, increased NF-κB trans-activity, but not for IκB degradation or NF-κB nuclear translocation, suggesting a role for p38 MAPK in the modification of NF-κB. DDR1b-mediated IκB degradation was mediated through the recruitment of the adaptor protein Shc to the LXNPXY motif of the receptor and the downstream TNFR-associated factor 6/NF-κB activator 1 signaling cascade. Taken together, our study has identified NF-κB as a novel target of DDR1b signaling and provided a novel mechanism by which tissue-infiltrating macrophages produce large amounts of chemokines during the development of inflammatory diseases. Intervention of DDR1b signaling may be useful to control inflammatory diseases in which these proteins play an important role.

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

“…In our ER stress model, activation of p38 MAPK may be involved in enhancing nuclear NF-B DNA binding activity because inhibition of p38 MAPK decreases the DNA binding activity of NF-B with minor effects on nuclear translocation of NF-B subunits. Recently, p38 MAPK was shown to activate the NF-B transcriptional activity without affecting its nuclear translocation (53,54), which may be similar to the role of p38 MAPK in this report. The appearance of NF-B in the nucleus began 1.5 h after ER stress which is consistent with the induction of COX-2 mRNA.…”

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

“…In T cells, IFN-␥ expression is dependent on p38 MAPK, a key pathway activated by DDR1. 20,27,34 Alternatively to a role of DDR1 in macrophage migration, but not exclusively, the proinflammatory chemotactic environment may consequently be influenced by DDR1 expression in resident and/or infiltrating cells in UUO.…”

Collagens in the progression and complications of atherosclerosis

“…However, overexpression of DDR1a promoted invasion of these cells through collagen matrices, 71 while overexpression of DDR1b promoted cell differentiation and increased cytokine production via the activation of p38 and NFκB. 74,75 Less is known about the function of DDR2; however, DDR2 was upregulated on mature bone marrow-derived dendritic cells, and promoted antigen uptake and presentation, and cytokine secretion. 76 Taken together, these studies support a role for collagen signaling through DDRs as a key mediator of macrophage and dendritic cell biology.…”