IL-17 Producing γδ T Cells are Required for a Controlled Inflammatory Response after Bleomycin-induced Lung Injury

Braun, Ruedi K.; Ferrick, Christina; Neubauer, Paul; Sjoding, Michael W.; Sterner-Kock, Anja; Kock, Martin; Putney, Lei; Ferrick, David A.; Hyde, Dallas M.; Love, Robert B.

doi:10.1007/s10753-008-9062-6

Cited by 119 publications

(104 citation statements)

References 61 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a chronic B. subtilis infection, mice lacking ␥␦ T cells demonstrated an enhanced fibrotic phenotype 24 because of enhanced inflammation. In support of our study, Braun et al 36 recently showed that mice lacking ␥␦ T cells had slower epithelial repair in response to bleomycin treatment.…”

Section: Discussionsupporting

confidence: 91%

“…Previous studies 37,38 have shown that ␥␦ T cells promote epithelial repair in skin and intestine through the production of fibroblast growth factor 7, also known as keratinocyte growth factor. However, similar to other pulmonary injury models, 22,36 the current study did not detect any differences in keratinocyte growth factor between ␥␦ KO mice and WT mice (data not shown). However, cytokine and chemokine analysis of lung homogenate demonstrated that ␥␦ KO mice were deficient in the chemokines CXCL1, IL-6, G-CSF, and CXCL10.…”

Section: Discussionsupporting

confidence: 88%

“…34 In line with the current studies, there is growing literature that certain subsets of T cells are beneficial because mice with severe combined immunodeficiency developed more severe fibrosis in response to asbestos, which was reduced on reconstitution with T cells. 11 Furthermore, use of mice deficient in natural killer T cells 35 or ␥␦ T cells 36 has shown worsened fibrosis, suggesting that specific subsets of T cells are responsible for regulating fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…However, histological features demonstrate pronounced hypercellularity and intimal thickening in lung parenchyma. Braun et al 36 have shown that ␥␦ KO mice have greater volume density (a measure of alveolar septal thickening) after bleomycin exposure. It is likely that the inflammatory differences seen between ␥␦ KO mice and WT mice are compartmental, and these findings suggest that ␥␦ T cells are Figure 7.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Pociask

Chen

Choi

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

␥␦ T cells are a subset of T cells associated with epithelial mucosal tissues and play a prominent role in both promoting and dampening inflammatory responses to pathogens; in addition, they strongly mediate epithelial repair. By using a bleomycin model of pulmonary fibrosis, we found that ␥␦ T-cell populations dramatically increased after bleomycin administration. To determine the importance of these cells, we exposed mice lacking the ␦ chain of the ␥␦ T-cell receptor (␥␦ knockout [KO]) to bleomycin. Pulmonary fibrosis was more severe in ␥␦ KO mice, as measured by collagen deposition (hydroxyproline) and histopathological features. Furthermore, there was no evidence of resolution of the fibrotic response up to 45 days after bleomycin therapy. In contrast to control mice, ␥␦ KO mice had decreased concentrations of IL-6, granulocyte colony stimulating factor, chemokine CXC ligand (CXCL) 1, and interferon inducible protein 10/CXCL10. In vitro culture of ␥␦ T cells purified from lungs 17 days after bleomycin exposure (a time of peak influx of these cells) demonstrated that ␥␦ T cells produced substantial quantities of all four of these cytokines, suggesting that ␥␦ T cells are a predominant source of these proteins. To demonstrate that ␥␦ T cells are effector cells in the fibrotic response, we performed adoptive transfer experiments with ␥␦ T cells sorted from bleomycin-treated lungs; these cells were sufficient to resolve fibrosis in ␥␦ KO mice and restore CXCL10 levels comparable to wild-type mice. Furthermore, overexpression of CXCL10 in the lung decreased the severity of fibrosis seen in the ␥␦ KO mice. Finally, adoptive transfer of ␥␦ T cells from CXCL10 ؊/؊ mice failed to reverse the severe fibrosis in ␥␦ KO mice. These results indicate that ␥␦ T cells promote the resolution of fibrosis through the production of

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Pociask

Chen

Choi

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Consistent with our results, gd T cells in the lungs of WT mice were found to predominantly produce IL-17, and the amount of hydroxyproline in the lungs increased in gd T cell-deficient mice during BIPF (41). In contrast, in a recent study, IL-17A produced by CD4 + and gd + T cells promoted bleomycin and IL-1b-mediated pulmonary fibrosis (42).…”

Section: Discussionsupporting

confidence: 90%

TLR2-Mediated Production of IL-27 and Chemokines by Respiratory Epithelial Cells Promotes Bleomycin-Induced Pulmonary Fibrosis in Mice

Kim

Akira

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis is a fatal disease characterized by progressive destruction of the lung. Although TLR2 bridges innate and adaptive immunity by sensing tissue damage, its role in pulmonary fibrosis remains unclear. To address this issue, TLR2−/− and WT mice were examined for bleomycin-induced pulmonary fibrosis (BIPF). Flow cytometric and immunohistochemical analysis revealed that TLR2 expression in bronchial epithelial and immune cells of the lungs was upregulated in WT mice during BIPF. Levels of IL-27, TGF-β, chemokines, and hydroxyproline were lower in lungs of TLR2−/− mice than in those of WT mice, but IL-17 levels were higher in TLR2−/− mice. In in vivo experiments using bone marrow-chimeric mice, TLR2 expression on respiratory epithelial cells, rather than immune cells, induced IL-27 and chemokine production in the lungs, further stimulating BIPF. This effect of TLR2 depended on IRF complexes and MyD88. BIPF was more severe in IL-17A−/− mice and in TLR2−/− mice treated with anti–IL-17 mAb than in TLR2−/− and WT mice. Furthermore, IL-27 blockade in WT mice reduced hydroxyproline levels by enhancing IL-17 production, whereas the treatment of TLR2−/− mice with a chemokine mixture increased hydroxyproline levels by recruiting inflammatory cells into the lungs. TLR2 signaling promotes BIPF by inducing IL-27 and chemokine production by respiratory epithelial cells, thereby inhibiting IL-17 production and recruiting inflammatory cells into the lungs.

show abstract

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Carvalheiro

Affandi

Malvar‐Fernández

et al. 2019

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc). Methods Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme‐linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6–7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5–7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay. Results Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up‐regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors. Conclusion Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc.

show abstract

IL-17 Producing γδ T Cells are Required for a Controlled Inflammatory Response after Bleomycin-induced Lung Injury

Abstract: Mouse gammadelta T cells produce IL-17 in response to lung injury and are required for an organized inflammatory response and epithelial repair. The lack of gammadelta T cells correlates with increased inflammation and fibrosis.

Cited by 119 publications

References 61 publications

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

TLR2-Mediated Production of IL-27 and Chemokines by Respiratory Epithelial Cells Promotes Bleomycin-Induced Pulmonary Fibrosis in Mice

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Contact Info

Product

Resources

About