The CCL2 synthesis inhibitor bindarit targets cells of the neurovascular unit, and suppresses experimental autoimmune encephalomyelitis

Ge, Shujun; Shrestha, Bandana; Paul, Debayon; Keating, Carolyn E.; Cone, Robert E.; Guglielmotti, Angelo; Pachter, Joel S.

doi:10.1186/1742-2094-9-171

Cited by 54 publications

(41 citation statements)

References 82 publications

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“…Bindarit has been reported to reduce symptoms in several animal models of human disease, such as adjuvant-induced arthritis (43), breast cancer (44), autoimmune encephalitis (45), severe acute pancreatitis (46), and lupus nephritis (47), through potent suppression of CCL2 transcription. Although CCL2 is the best characterized target of bindarit, it also inhibits other inflammatory mediators, such as CCL8, CCL7, and interleukin-12 (IL-12) (48).…”

mentioning

confidence: 99%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

108

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The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (CT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-B ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.

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mentioning

confidence: 99%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

108

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“…33 34 While vehicle-treated mice developed severe OA, mice treated with bindarit for 12 weeks exhibit markedly diminished cartilage damage (figure 6A, B), synovitis and osteophyte formation (see online supplementary figure S6A,B). In addition, bindarit treatment significantly reduced macrophage accumulation in mouse knee joints (figure 6C, D).…”

Section: Resultsmentioning

confidence: 99%

“…We show that CCL2 secretion can be abrogated using bindarit, a synthetic molecule previously shown to potently and selectively inhibit expression of the monocyte chemoattractants CCL2, CCL8 and CCL7 as well as attenuate inflammation in various mouse models of inflammatory disease including experimental autoimmune encephalomyelitis (EAE) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis 29 34. We provide proof of concept that pharmacological suppression of CCL2 expression using bindarit is effective in reducing inflammation, cartilage damage and monocyte/macrophage accumulation in mouse OA.…”

Section: Discussionmentioning

confidence: 99%

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis

et al. 2016

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Objectives While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/ CCR5 chemokine axes in OA pathogenesis. Methods Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains. Results Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA. Conclusions Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

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“…Bindarit has been shown some clinical efficacy in treating a broad array of experimental inflammatory, autoimmune and vascular disorders; it also had some success in recent clinical trials for diabetic nephropathy and lupus nephritis (48). …”

Section: Methodsmentioning

confidence: 99%

“…The method for bindarit treatment in animals has been previously described (48). Briefly, bindarit was prepared as a suspension in dimethyl sulfoxide (DMSO) at a concentration of 40 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

Thiamine Deficiency Promotes T Cell Infiltration in Experimental Autoimmune Encephalomyelitis: The Involvement of CCL2

Fan

Zhang

et al. 2014

The Journal of Immunology

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Multiple sclerosis (MS) is a complex multifactorial disease that results from the interplay between environmental factors and a susceptible genetic background. Experimental autoimmune encephalomyelitis (EAE) has been widely used to investigate the mechanisms underlying MS pathogenesis. Chemokines, such as C-C Chemokine Ligand 2 (CCL2), are involved in the development of EAE. We have previously shown that thiamine deficiency (TD) induced CCL2 in neurons. We hypothesized that TD may affect the pathogenesis of EAE. In this study, EAE was induced in C57BL/6J mice by the injection of myelin oligodendroglial glycoprotein (MOG) peptide 35–55 with/without TD. TD aggravated the development of EAE which was indicated by clinical scores and pathological alterations in the spinal cord. TD also accelerated the development of EAE in an adoptive transfer EAE model. TD caused microglial activation and a drastic increase (up 140%) in leukocyte infiltration in the spinal cord of the EAE mice; specifically TD increased Th-1 and Th-17 cells. TD upregulated the expression of CCL2 and its receptor CCR2 in the spinal cord of EAE mice. Cells in peripheral lymph node and spleen isolated from MOG-primed TD mice showed much stronger proliferative responses to MOG. CCL2 stimulated the proliferation and migration of T lymphocytes in vitro. Our results suggested that TD exacerbated the development of EAE through activating CCL2 and inducing pathological inflammation.

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The CCL2 synthesis inhibitor bindarit targets cells of the neurovascular unit, and suppresses experimental autoimmune encephalomyelitis

Cited by 54 publications

References 82 publications

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis

Thiamine Deficiency Promotes T Cell Infiltration in Experimental Autoimmune Encephalomyelitis: The Involvement of CCL2

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