It has been shown that interleukin (IL)-17 is important in the pathogenesis of animal models of Rheumatoid Arthritis (RA). However, the mechanism by which IL-17 promotes disease is incompletely understood. The TH- 17 cell, a new lineage of CD4+ T cells distinct from TH1 and TH2 is characterized by the production of IL-17. We identified increased numbers of TH-17 cells in RA synovial fluid (SF) compared to normal peripheral blood (PB). Adenovirally transferred IL-17 induced in vivo monocyte recruitment into the peritoneal cavity. IL-17, in the absence of other mediators, was chemotactic for monocytes at the concentrations detected in the RA SF. IL-17-induced monocyte migration was abrogated by neutralizing IL-17 receptor (R). We also demonstrated that IL-17 immunodepletion significantly reduced monocyte chemotaxis induced by RA SF compared to sham immunodepletion. The indirect effects of IL-17 on monocyte chemotaxis were also examined. RA synovial tissue (ST) fibroblasts and in vitro differentiated macrophages (IVD M$s) activated by IL-17 produced both MCP-1 and CCL20 while CXCL16 was only induced in M$s. Based on our preliminary data we hypothesize that IL-17 can induce monocyte transendothelial migration into the RA ST directly by altering integrin conformation on monocytes and thereby increasing their binding affinity to their cognate ligands on endothelium. Further, we hypothesize that IL-17 mediates monocyte recruitment into the synovium by inducing MCP-1 production by endothelial cells. The goal of this proposal is to examine whether IL-17-induced monocyte migration into the RA ST is through direct effects of IL-17 on monocytes or through the indirect effects of IL-17 mediated by chemokines and/or integrins produced by endothelial cells or perhaps both.
The specific aims of this proposal are 1: a. Determine whether IL-17 promotes monocyte recruitment into RA ST engrafted in the severe combined immune deficiency (SCID) mice;b. Investigating whether IL-17R blockade on monocytes prevents their homing to engrafted RA ST in SCID mice in response to IL-17;2: a. Examine whether IL-17 can induce monocyte chemoattractant chemokines from the endothelial cells;b. Investigate whether IL-17 induces adhesion molecule activation (LFA1, VLA4) and expression (LFA1, VLA4) on monocytes, and endothelial cells (ICAM1 and VCAM1) or both;c. Investigate whether IL-17-induced monocyte transendothelial migration in laminar flow depends on its effect on adhesion molecules expressed on monocytes, endothelial cells or both. Successful completion of the proposed research will elucidate the mechanism by which IL-17 mediates monocyte recruitment into the RA ST. Those factors that regulate IL-17- induced monocyte migration may be potential therapeutic targets in RA.
Project Narrative. In rheumatoid arthritis (RA), migration of a type of immune cells called monocytes into the joint contributes to inflammation. In this proposal we demonstrate novel data showing that a pro-inflammatory cell signaling protein called IL-17 is important in the migration of monocytes, and that this effect occurs at the concentrations of IL-17 present in RA joint fluid. Successful completion of the proposed research will elucidate the mechanism by which IL-17 mediates monocyte migration in RA joint tissue. Those factors that regulate IL- 17-induced monocyte migration may be potential therapeutic targets in RA.
|Elshabrawy, Hatem A; Volin, Michael V; Essani, Abdul B et al. (2018) IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells. Angiogenesis 21:215-228|
|Elshabrawy, Hatem A; Essani, Abdul E; Szekanecz, Zoltán et al. (2017) TLRs, future potential therapeutic targets for RA. Autoimmun Rev 16:103-113|
|Kim, Seung-Jae; Chen, Zhenlong; Essani, Abdul B et al. (2016) Identification of a Novel Toll-like Receptor 7 Endogenous Ligand in Rheumatoid Arthritis Synovial Fluid That Can Provoke Arthritic Joint Inflammation. Arthritis Rheumatol 68:1099-110|
|Chen, Zhenlong; Kim, Seung-Jae; Essani, Abdul B et al. (2015) Characterising the expression and function of CCL28 and its corresponding receptor, CCR10, in RA pathogenesis. Ann Rheum Dis 74:1898-906|
|Elshabrawy, Hatem A; Chen, Zhenlong; Volin, Michael V et al. (2015) The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18:433-48|
|Kim, Seung-Jae; Chen, Zhenlong; Chamberlain, Nathan D et al. (2014) Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis. J Immunol 193:3902-13|
|Kim, Seung-Jae; Chen, Zhenlong; Chamberlain, Nathan D et al. (2013) Angiogenesis in rheumatoid arthritis is fostered directly by toll-like receptor 5 ligation and indirectly through interleukin-17 induction. Arthritis Rheum 65:2024-36|
|Pope, Richard M; Shahrara, Shiva (2013) Possible roles of IL-12-family cytokines in rheumatoid arthritis. Nat Rev Rheumatol 9:252-6|
|Chen, Zhenlong; Kim, Seung-jae; Chamberlain, Nathan D et al. (2013) The novel role of IL-7 ligation to IL-7 receptor in myeloid cells of rheumatoid arthritis and collagen-induced arthritis. J Immunol 190:5256-66|
|Chamberlain, Nathan D; Kim, Seung-jae; Vila, Olga M et al. (2013) Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNF? in monocytes. Ann Rheum Dis 72:418-26|
Showing the most recent 10 out of 21 publications