Homogeneous Inflammatory Gene Profiles Induced in Human Dermal Fibroblasts in Response to the Three Main Species of Borrelia burgdorferi sensu lato

Meddeb, Mariam; Carpentier, Wassila; Cagnard, Nicolas; Nadaud, Sophie; Grillon, Antoine; Barthel, Cathy; Martino, Sylvie Josiane De; Jaulhac, B.; Boulanger, Nathalie; Schramm, Frédéric

doi:10.1371/journal.pone.0164117

Cited by 17 publications

(36 citation statements)

References 45 publications

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“…burgdorferi alone, the 68 differentially expressed genes included those associated with immune disorders, inflammatory pathways, and infectious diseases (Figure a). These results were similar to a previously published report using dermal fibroblasts stimulated with various Borrelia strains (Meddeb et al, ).…”

Section: Resultssupporting

confidence: 93%

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Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Lochhead

Ordóñez

Arvikar

et al. 2019

Cellular Microbiology

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Lyme arthritis (LA), a late disease manifestation of Borrelia burgdorferi infection, usually resolves with antibiotic therapy. However, some patients develop proliferative synovitis lasting months to several years after spirochetal killing, called postinfectious LA. In this study, we phenotyped haematopoietic and stromal cell populations in the synovial lesion ex vivo and used these findings to generate an in vitro model of LA using patient‐derived fibroblast‐like synoviocytes (FLS). Ex vivo analysis of synovial tissue revealed high abundance of IFNγ‐producing T cells and NK cells. Similar to marked IFNγ responses in tissue, postinfectious LA synovial fluid also had high levels of IFNγ. HLA‐DR‐positive FLS were present throughout the synovial lesion, particularly in areas of inflammation. FLS stimulated in vitro with B. burgdorferi, which were similar to conditions during infection, expressed 68 genes associated primarily with innate immune activation and neutrophil recruitment. In contrast, FLS stimulated with IFNγ, which were similar to conditions in the postinfectious phase, expressed >2,000 genes associated with pathogen sensing, inflammation, and MHC Class II antigen presentation, similar to the expression profile in postinfectious synovial tissue. Furthermore, costimulation of FLS with B. burgdorferi and IFNγ induced greater expression of IL‐6 and other innate immune response proteins and genes than with IFNγ stimulation alone. These results suggest that B. burgdorferi infection, in combination with IFNγ, initiates the differentiation of FLS into a highly inflammatory phenotype. We hypothesise that overexpression of IFNγ by lymphocytes within synovia perpetuates these responses in the postinfectious period, causing proliferative synovitis and stalling appropriate repair of damaged tissue.

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Section: Resultssupporting

confidence: 93%

“…These results were similar to a previously published report using dermal fibroblasts stimulated with various Borrelia strains (Meddeb et al, 2016).…”

Section: Abundance Of Hla-dr-positive Fls In Synovial Tissuesupporting

confidence: 93%

Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Lochhead

Ordóñez

Arvikar

et al. 2019

Cellular Microbiology

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“…10 , 11 , 12 , 13 We recently described how epithelial stress, via release of IL-1α, triggers the polarization of lung fibroblasts toward a proinflammatory phenotype characterized by their highly abundant secretion of IL-6, IL-8, chemokine (C-C motif) ligand (CCL) 2 (monocyte chemoattractant protein-1), and granulocyte-macrophage colony-stimulating factor. 14 , 15 Similar inflammatory cytokine release has also been described in hepatic stellate cells, 16 cardiac fibroblasts, 17 dermal fibroblasts, 18 and fibroblasts isolated from the knee, 19 suggesting the ability to adopt an immunomodulatory state may be a ubiquitous property of fibroblasts. Herein, we hypothesized that fibroblasts persisting within fibrotic microenvironments may be a source of stress-induced inflammatory exacerbations and pain.…”

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confidence: 57%

Fibroblasts Promote Inflammation and Pain via IL-1α Induction of the Monocyte Chemoattractant Chemokine (C-C Motif) Ligand 2

Paish

Kalson

Smith

et al. 2018

The American Journal of Pathology

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Fibroblasts persist within fibrotic scar tissue and exhibit considerable phenotypic and functional plasticity. Herein, we hypothesized that scar-associated fibroblasts may be a source of stress-induced inflammatory exacerbations and pain. To test this idea, we used a human model of surgery-induced fibrosis, total knee arthroplasty (TKA). Using a combination of tissue protein expression profiling and bioinformatics, we discovered that many months after TKA, the fibrotic joint exists in a state of unresolved chronic inflammation. Moreover, the infrapatellar fat pad, a soft tissue that becomes highly fibrotic in the post-TKA joint, expresses multiple inflammatory mediators, including the monocyte chemoattractant, chemokine (C-C motif) ligand (CCL) 2, and the innate immune trigger, IL-1α. Fibroblasts isolated from the post-TKA fibrotic infrapatellar fat pad express the IL-1 receptor and on exposure to IL-1α polarize to a highly inflammatory state that enables them to stimulate the recruitment of monocytes. Blockade of fibroblast CCL2 or its transcriptional regulator NF-κB prevented IL-1α–induced monocyte recruitment. Clinical investigations discovered that levels of patient-reported pain in the post-TKA joint correlated with concentrations of CCL2 in the joint tissue, such that the chemokine is effectively a pain biomarker in the TKA patient. We propose that an IL-1α–NF-κB–CCL2 signaling pathway, operating within scar-associated fibroblasts, may be therapeutically manipulated for alleviating inflammation and pain in fibrotic joints and other tissues.

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“…However, the role of the genospecies-specific immune response has not been studied in detail. In the recent past, human dermal fibroblasts co-cultured with the three main B. burgdorferi sensu lato species showed a homogenous inflammatory gene profile with similar transcriptional profiles and no species-specific fingerprint of transcriptional changes in fibroblasts, including a common core of chemokines/cytokines and interferon-related genes [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Co-culture of human fibroblasts and Borrelia burgdorferi enhances collagen and growth factor mRNA

et al. 2017

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Skin fibrosis has been reported in Borrelia burgdorferi infection in Europe, but has been questioned by several authors. The objective of the present study was to examine the interaction of skin fibroblasts with B. burgdorferi sensu stricto B31 (BB) and B. afzelii (BA) in vitro by electron microscopy. We also determined the expression of collagen type I, TGF-β, FGF-1, calreticulin (CALR), decorin (DCN), and PDGF-α at the mRNA level in Borrelia/fibroblast co-cultures. Intact Borrelia attach to and transmigrate fibroblasts, and undergo cystic transformation outside the fibroblasts. Fibroblasts preserve their vitality and express a prominent granular endoplasmic reticulum, suggesting activated protein synthesis. On two different semi-quantitative real-time PCR assays, BB- and BA/fibroblast co-cultures showed a significant induction of type I collagen mRNA after 2 days compared to fibroblasts (fourfold for BA and 1.8-fold for BB; p < 0.02). In addition, there was a significant upregulation of mRNA expression of TGF-β, CALR, PDGF-α, and DCN in BA and BB co-cultures compared to control fibroblasts in monolayer cultures after 2 days (p < 0.01). The BA/fibroblast co-culture induced a considerably greater upregulation of collagen and growth factor mRNA compared to BB/fibroblast co-culture. In contrast, a significant down-regulation of FGF-1 (20-fold for BA and 4.5-fold for BB) mRNA expression was detected in co-cultures compared to controls (p < 0.01). The results of the study support the hypothesis that BB sensu lato, and BA in particular, enhances collagen mRNA expression and can stimulate growth factors responsible for increased collagen production.

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Homogeneous Inflammatory Gene Profiles Induced in Human Dermal Fibroblasts in Response to the Three Main Species of Borrelia burgdorferi sensu lato

Cited by 17 publications

References 45 publications

Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Fibroblasts Promote Inflammation and Pain via IL-1α Induction of the Monocyte Chemoattractant Chemokine (C-C Motif) Ligand 2

Co-culture of human fibroblasts and Borrelia burgdorferi enhances collagen and growth factor mRNA

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