Targeting the chemotactic function of CD147 reduces collagen‐induced arthritis

Damsker, Jesse M.; Okwumabua, Ifeanyi; Pushkarsky, Tatiana; Arora, Kamalpreet; Bukrinsky, Michael; Constant, Stephanie L.

doi:10.1111/j.1365-2567.2008.02877.x

Cited by 80 publications

(88 citation statements)

References 31 publications

(43 reference statements)

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“…Indeed, the inflammatory response in BA, both in the mouse model and in humans, is associated with infiltration by neutrophils, which form inflammatory foci around the areas of bile duct obstruction (21)(22)(23). Modulation of neutrophil infiltration by the inhibition of extracellular cyclophilins or their receptor CD147 has been reported in rheumatoid arthritis (38,39), lung inflammation (14) and myocardial ischemia and reperfusion injury (40). The decreased migration of neutrophils and other inflammatory cells to the liver may explain the decreased levels of IL-6 observed in MM284-treated animals in our study.…”

Section: Discussionmentioning

confidence: 99%

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders.

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Section: Discussionmentioning

confidence: 99%

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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“…This finding suggests that EMMPRIN may also affect leukocyte recruitment or their adhesion onto cerebral vessels, thereby generally reducing the number of inflammatory cells that attach onto cerebral vessels. In this regard, EMMPRIN is known to interact with the cyclophilins that can alter leukocyte chemotaxis (Damsker et al, 2009). Moreover, EMMPRIN colocalizes with integrins (Berditchevski et al, 1997) expressed on endothelial cells of blood vessels and infiltrating T-cells, and it is possible that anti-EMMPRIN treatment may alter integrin function and thereby affect the adhesion of leukocytes onto endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Agrawal¹,

Silva²,

Tourtellotte³

et al. 2011

J. Neurosci.

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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the Ig superfamily, with various physiological roles including the induction of matrix metalloproteinases (MMPs), leukocyte activation, and tumor progression. In this study, we illustrate a novel involvement of EMMPRIN in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We found EMMPRIN levels to be upregulated on peripheral leukocytes before onset of EAE clinical signs and on infiltrating leukocytes and resident cells within the CNS in symptomatic mice. In EAE brain sections, EMMPRIN expression was localized with MMP-9 protein and activity. The increased EMMPRIN level was also characteristic of brain samples from MS subjects, particularly in plaque-containing areas. To evaluate the implications of elevated EMMPRIN levels, we treated EAE mice with an EMMPRIN function-blocking antibody and found reduced EAE clinical severity accompanied by decreased CNS parenchymal infiltration of leukocytes. Amelioration of EAE clinical signs by the anti-EMMPRIN antibody was critically dependent on its administration around the period of onset of clinical signs, which is typically associated with significant influx of leukocytes into the CNS. Moreover, the reduction in disease severity in anti-EMMPRINtreated mice was associated with diminished MMP proteolytic activity at the glia limitans, the final barrier before parenchymal infiltration of leukocytes. Together, our results are the first to emphasize a role for EMMPRIN in MS and EAE, whereby EMMPRIN regulates leukocyte trafficking through increasing MMP activity. These results identify EMMPRIN as a novel therapeutic target in MS.

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“…CD147 is a receptor that mediates the actions of extracellular CypA [e.g., an anti-CD147 Ab completely prevents CypA-induced chemotaxis of neutrophils (15)]. In vivo, inhibition of CD147 reduces allergic inflammation in mouse models of asthma (14), collagen-induced arthritis (21), and sepsis-induced acute kidney injury (22). Although these in vivo effects have been attributed to CypA antagonism, there are other ligands that activate CD147, such as E-selectin (23).…”

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confidence: 99%

Cyclophilin A Is a Damage-Associated Molecular Pattern Molecule That Mediates Acetaminophen-Induced Liver Injury

Dear

Simpson

Nicolai

et al. 2011

The Journal of Immunology

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The immune system is alerted to cell death by molecules known as damage-associated molecular patterns (DAMPs). These molecules partly mediate acetaminophen-induced liver injury, an archetypal experimental model of sterile cell death and the commonest cause of acute liver failure in the western world. Cyclophilin A (CypA) is an intracellular protein that is proinflammatory when released by cells. We hypothesized that CypA is released from necrotic liver cells and acts as a DAMP to mediate acetaminophen-induced liver injury. Our data demonstrated that mice lacking CypA (Ppia−/−) were resistant to acetaminophen toxicity. Antagonism of the extracellular receptor for CypA (CD147) also reduced acetaminophen-induced liver injury. When injected into a wild-type mouse, necrotic liver from Ppia−/− mice induced less of an inflammatory response than did wild-type liver. Conversely, the host inflammatory response was increased when CypA was injected with necrotic liver. Antagonism of CD147 also reduced the inflammatory response to necrotic liver. In humans, urinary CypA concentration was significantly increased in patients with acetaminophen-induced liver injury. In summary, CypA is a DAMP that mediates acetaminophen poisoning. This mechanistic insight presents an opportunity for a new therapeutic approach to a disease that currently has inadequate treatment options.

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Targeting the chemotactic function of CD147 reduces collagen‐induced arthritis

Cited by 80 publications

References 31 publications

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Cyclophilin A Is a Damage-Associated Molecular Pattern Molecule That Mediates Acetaminophen-Induced Liver Injury

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