<i>Borrelia burgdorferi-</i>Induced Expression of Matrix Metalloproteinases from Human Chondrocytes Requires Mitogen-Activated Protein Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathways

Lyme borreliosis is a tick-borne bacterial infection that in many cases is limited to the skin. However, in some patients the bacterium evades the immune response and disseminates into various organs. Dendritic cells (DCs) are among the first cells to meet invading pathogens in the skin. We have previously shown that CD38, an ectoenzyme involved in the migration of DCs and generally upregulated by microbial stimuli, is not upregulated in Borrelia garinii-stimulated DCs. In this paper, we characterize the cellular events that lead to the absence of CD38 on the DC surface after B. garinii stimulation and investigate the consequences of absent CD38 expression for the migration of DCs in vitro and in vivo. The data show that 1) effective signaling via p38 MAPK (and STAT1 and NF-κB) is needed for CD38 expression and 2) TLR2 stimulation, as opposed to TLR4 stimulation, does not induce IFN-β autocrine loop-dependent expression of CD38 and secretion of IL-12. Further, we show that 3) B. garinii-stimulated DCs do not migrate effectively toward CCL19 and CCL21 and 4) after B. garinii infection of mice, the number of DCs migrating from the infection site to draining lymph nodes is only half that induced by Escherichia coli infection. Our results provide evidence for the first time that different TLR use results in different CD38 expression, which correlates with the migratory potential of DCs.

Section: Discussionmentioning

confidence: 99%

TLR2 Utilization ofBorreliaDoes Not Induce p38- and IFN-β Autocrine Loop-Dependent Expression of CD38, Resulting in Poor Migration and Weak IL-12 Secretion of Dendritic Cells

Hartiala

Hytönen²,

Yrjänäinen³

et al. 2010

“…MMP-3 and MMP-19 are elevated in the joints of mice that develop arthritis in response to infection with B. burgdorferi, and levels of these MMPs correlate closely with the severity of arthritis seen in different strains of mice in response to infection (12). Induction of these MMPs appears to be mediated by multiple signaling pathways, including p38 MAPK, JNK, and JAK/STAT pathways (13). However, the receptors that are responsible for activation of these signaling pathways in joint tissue remain unknown.…”

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

confidence: 99%

“…Having determined that TLR-2 was expressed in the chondrocyte cells, we next added a known TLR-2 ligand, lipidated OspA of B. burgdorferi, to in vitro cultures of chondrocytes. We have shown previously that MMP-1 and MMP-3 production by HC cells infected with B. burgdorferi is transcriptionally regulated, so we examined induction of MMP-1 and MMP-3 mRNA using q-RT-PCR (13). Addition of the B. burgdorferi lipoprotein OspA does induce expression of both MMP-1 and MMP-3 from HC, suggesting a role for TLR-2.…”

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

confidence: 99%

“…cDNA samples contaminated by genomic DNA were discarded, and the original RNA was treated with DNase before the reverse-transcriptase reaction was repeated. Quantitation of cDNA from specific mRNA transcripts was accomplished by quantitative rt-RT-PCR (Bio-Rad) by using SYBR Green technology (Quantitect SYBR Green PCR kit; Qiagen), as previously described (13,29). ␤-Actin and nidogen genes were used as internal control for human and murine samples, respectively.…”

Section: Quantitative (Q)-rt-pcrmentioning

confidence: 99%

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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

Self Cite

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.

“…These interactions are further enhanced by the binding of lipoproteins to CD14 (26,27), which can increase the sensitivity of TLR2-lipoprotein interactions at physiological levels and augment TLR2-mediated activation (28). This lipoprotein-mediated signaling leads to the rapid activation of NF-B (29, 30)-and MAPK-signaling pathways (31,32), and the subsequent up-regulation of multiple proinflammatory cytokines and chemokines from many of the cell and tissue types associated with Lyme pathology (33)(34)(35)(36)(37). Deficiencies in these lipoproteinmediated signaling pathways has significant effects on the ability to control spirochete numbers in multiple target tissues (23)(24)(25)38), highlighting the importance of these innate immune responses in host control of B. burgdorferi infections.…”

mentioning

confidence: 99%

IL-10 Deficiency Promotes Increased Borrelia burgdorferi Clearance Predominantly through Enhanced Innate Immune Responses

Lazarus

Meadows

Lintner

et al. 2006

Borrelia burgdorferi is capable of persistently infecting a variety of hosts despite eliciting potent innate and adaptive immune responses. Preliminary studies indicated that IL-10-deficient (IL-10−/−) mice exhibit up to 10-fold greater clearance of B. burgdorferi from target tissues compared with wild-type mice, establishing IL-10 as the only cytokine currently known to have such a significant effect on spirochetal clearance. To further delineate these IL-10-mediated immune effects, kinetic studies indicated that spirochete dissemination to target tissues is similar in both wild-type and IL-10−/− mouse strains, and that enhanced clearance of B. burgdorferi in IL-10−/− mice is correlated with increased B. burgdorferi-specific Ab as early as 2 wk postinfection. Immunoblot analysis indicated that Abs produced by infected IL-10−/− and wild-type mice recognize similar ranges of spirochetal Ags. Immune sera from IL-10−/− and wild-type mice also exhibited similar bactericidal activity in vitro, and passive transfer of these immune sera into B. burgdorferi-infected SCID mice caused similar reductions of bacterial numbers in target tissues. Infectious dose studies indicated that 8-fold more B. burgdorferi were needed to efficiently infect naive IL-10−/− mice, suggesting these animals possess higher innate barriers to infection. Moreover, macrophages derived from IL-10−/− mice exhibit enhanced proinflammatory responses to B. burgdorferi stimulation compared with wild-type controls, and these responses are not significantly affected by the presence of immune serum. These findings confirm that B. burgdorferi clearance by innate immune responses is more efficient in the absence of IL-10, and these activities are not directly related to increased levels of B. burgdorferi-specific Ab.