Selective Induction of Matrix Metalloproteinases by<i>Borrelia burgdorferi</i>via Toll‐Like Receptor 2 in Monocytes

Gebbia, Joseph A.; Coleman, James L.; Benach, Jorge L.

doi:10.1086/380414

Cited by 64 publications

(53 citation statements)

References 49 publications

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“…Not only do these enzymes naturally occur in the blood circulation, but they are also expressed as a result of the interaction between host cells and B. burgdorferi. There have been several reports showing that astrocytes (69), chondrocytes (33,53), and monocytes (26,27) express MMPs in response to B. burgdorferi. These reports have also shown that the interaction of B. burgdorferi with host cells leads to the activation of plasminogen that activates these MMPs, thus facilitating the degradation of the extracellular matrix.…”

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confidence: 99%

Borrelia burgdorferi, Host-Derived Proteases, and the Blood-Brain Barrier

Grab¹,

et al. 2005

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Neurological manifestations of Lyme disease in humans are attributed in part to penetration of the blood-brain barrier (BBB) and invasion of the central nervous system (CNS) by Borrelia burgdorferi. However, how the spirochetes cross the BBB remains an unresolved issue. We examined the traversal of B. burgdorferi across the human BBB and systemic endothelial cell barriers using in vitro model systems constructed of human brain microvascular endothelial cells (BMEC) and EA.hy 926, a human umbilical vein endothelial cell (HUVEC) line grown on Costar Transwell inserts. These studies showed that B. burgdorferi differentially crosses human BMEC and HUVEC and that the human BMEC form a barrier to traversal. During the transmigration by the spirochetes, it was found that the integrity of the endothelial cell monolayers was maintained, as assessed by transendothelial electrical resistance measurements at the end of the experimental period, and that B. burgdorferi appeared to bind human BMEC by their tips near or at cell borders, suggesting a paracellular route of transmigration. Importantly, traversal of B. burgdorferi across human BMEC induces the expression of plasminogen activators, plasminogen activator receptors, and matrix metalloproteinases. Thus, the fibrinolytic system linked by an activation cascade may lead to focal and transient degradation of tight junction proteins that allows B. burgdorferi to invade the CNS.

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confidence: 99%

Borrelia burgdorferi, Host-Derived Proteases, and the Blood-Brain Barrier

Grab¹,

et al. 2005

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“…TLR-2 has been shown to be involved in B. burgdorferi induction of some, but not all, MMPs from human monocytes (14). We have shown previously that B. burgdorferi induces MMP-1 and MMP-3 from HC cells and that this induction involves MAPK (ERK1/2, p38 MAPK, and JNK) pathways that could potentially be activated through TLR-2 signaling (30 -33).…”

Section: Role Of Tlr-2 In B Burgdorferi-induced Expression Of Mmp-1 mentioning

confidence: 86%

“…However, the receptors that are responsible for activation of these signaling pathways in joint tissue remain unknown. Gebbia et al (14) have shown previously that TLR-2 is involved in the induction of MMP-9 from monocytes, but does not appear to be involved in the induction of MMP-1. MMP-9 has not been found to be elevated in the joints of humans or mice with Lyme arthritis (10).…”

Section: Identification Of a Tlr-independent Pathway For Borrelia Burmentioning

confidence: 96%

Identification of a TLR-Independent Pathway forBorrelia burgdorferi-Induced Expression of Matrix Metalloproteinases and Inflammatory Mediators through Binding to Integrin α3β1

Behera

Hildebrand

Uematsu

et al. 2006

The Journal of Immunology

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Borrelia burgdorferi stimulates a robust inflammatory response at sites of localization. Binding of borrelial lipoproteins to TLR-2 is one pathway important in the host response to B. burgdorferi. However, while TLR-2 is clearly important in control of infection, inflammation is actually worsened in the absence of TLR-2 or the shared TLR adapter molecule, MyD88, suggesting that there are alternative pathways regulating inflammation. Integrins are cell surface receptors that play an important role in cell to cell communications and that can activate inflammatory signaling pathways. In this study, we report for the first time that B. burgdorferi binds to integrin α3β1 and that binding of B. burgdorferi to this integrin results in induction of proinflammatory cytokines, chemokines, and end-effector molecules such as matrix metalloproteinases in primary human chondrocyte cells. Expression of these same molecules is not affected by the absence of MyD88 in murine articular cartilage, suggesting that the two pathways act independently in activating host inflammatory responses to B. burgdorferi. B. burgdorferi-induced α3 signaling is mediated by JNK, but not p38 MAPK. In summary, we have identified a new host receptor for B. burgdorferi, integrin α3β1; binding of B. burgdorferi to integrin α3β1 results in the release of inflammatory mediators and is proposed as a TLR-independent pathway for activation of the innate immune response by the organism.

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“…Its upregulation in B. burgdorferi-stimulated macrophages is probably worthy of further investigation. MMP9, a granulocyte-secreted type IV collagenase (88), has been shown previously to be induced by B. burgdorferi in both human and murine monocytes in a TLR2-dependent manner (37,38). MMP9 is also upregulated in erythema migrans lesions of Lyme disease patients (99,100) and in joints of Lyme diseasesusceptible mice (7).…”

Section: Discussionmentioning

confidence: 97%