Joint Tissues Amplify Inflammation and Alter Their Invasive Behavior via Leukotriene B4 in Experimental Inflammatory Arthritis

Abstract

Mechanisms by which mesenchymal-derived tissue lineages participate in amplifying and perpetuating synovial inflammation in arthritis have been relatively underinvestigated and are therefore poorly understood. Elucidating these processes is likely to provide new insights into the pathogenesis of multiple diseases. Leukotriene B4 (LTB4) is a potent proinflammatory lipid mediator that initiates and amplifies synovial inflammation in the K/BxN model of arthritis. We sought to elucidate mechanisms by which mesenchymal-derived fibroblast-like synoviocytes (FLSs) perpetuate synovial inflammation. We focused on the abilities of FLSs to contribute to LTB4 synthesis and to respond to LTB4 within the joint. Using a series of bone marrow chimeras generated from 5-lipoxygenase–/– and leukotriene A4 (LTA4) hydrolase–/– mice, we demonstrate that FLSs generate sufficient levels of LTB4 production through transcellular metabolism in K/BxN serum-induced arthritis to drive inflammatory arthritis. FLSs—which comprise the predominant lineage populating the synovial lining—are competent to metabolize exogenous LTA4 into LTB4 ex vivo. Stimulation of FLSs with TNF increased their capacity to generate LTB4 3-fold without inducing the expression of LTA4 hydrolase protein. Moreover, LTB4 (acting via LTB4 receptor 1) was found to modulate the migratory and invasive activity of FLSs in vitro and also promote joint erosion by pannus tissue in vivo. Our results identify novel roles for FLSs and LTB4 in joints, placing LTB4 regulation of FLS biology at the center of a previously unrecognized amplification loop for synovial inflammation and tissue pathology.

Deficiency of Nrf2 Accelerates the Effector Phase of Arthritis and Aggravates Joint Disease

“…In addition, our previous research suggests the participation of another prostanoid pathway, PGD 2 , in the effector phase of this arthritis model (29). Joint inflammation is dependent on neutrophil recruitment via LTB 4 (6) which also stimulates synovial fibroblasts migration and invasion (7). In this study, the PGI 2 metabolite 6-ketoPGF 1a , PGD 2 , and LTB 4 were significantly increased in the serum of arthritic wild-type mice on day 10, compared with naïve animals, whereas the small increase in PGE 2 was not significant.…”

The 5-lipoxygenase/leukotriene pathway in obesity, insulin resistance, and fatty liver disease

“…Arachidonate 5-lipoxygenase knockout mice have been developed and shown to live normally and without appreciable dysfunction and to be protected against pulmonary inflammation and arthritis [16,17]. They are also protected against hyperlipidemia-dependent inflammation of the arterial wall and aortic aneurysms, although the precise contribution of 5-lipoxygenase to the pathogenesis of atherosclerosis is still under debate [18,19].…”

Lipid-cytokine-chemokine cascades orchestrate leukocyte recruitment in inflammation

“…Although 5-LO expression is restricted to myeloid cells, including neutrophils, eosinophils, monocytes/macrophages, and mast cells, LTA 4 H is widely expressed in hematopoietic and stromal tissues [32]. Thus, although LTB 4 biosynthesis ultimately depends on the activity of myeloid cells, other cell types can participate in the generation of LTB 4 in a transcellular manner by converting the myeloid cell-derived LTA 4 to LTB 4 [33,34]. As LTA 4 H is subject to suicide inactivation, the transcellular pathway of LTB 4 production may have biological significance in the amplification and sustainment of acute immune responses [33].…”

“…Thus, although LTB 4 biosynthesis ultimately depends on the activity of myeloid cells, other cell types can participate in the generation of LTB 4 in a transcellular manner by converting the myeloid cell-derived LTA 4 to LTB 4 [33,34]. As LTA 4 H is subject to suicide inactivation, the transcellular pathway of LTB 4 production may have biological significance in the amplification and sustainment of acute immune responses [33]. LTB 4 can bind to two highly conserved GPCRs, BLT1 and BLT2 [35][36][37].…”