Role for CXCR6 and Its Ligand CXCL16 in the Pathogenesis of T-Cell Alveolitis in Sarcoidosis

Agostini, Carlo; Cabrelle, Anna; Calabrese, Fiorella; Bortoli, Michela; Scquizzato, Elisa; Carraro, Samuela; Miorin, Marta; Beghè, Bianca; Trentin, Livio; Zambello, Renato; Facco, Monica; Semenzato, Gianpietro

doi:10.1164/rccm.200501-142oc

Cited by 83 publications

(85 citation statements)

References 28 publications

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“…The T-bet control of CXCR3 expression is of particular interest in sarcoidosis because this chemokine receptor plays a pivotal role in recruiting T-cells to the lungs with subsequent granuloma formation [4]. In this study, we observed a strong correlation between T-bet and CXCR3 and IFN-c expression in BAL cells obtained from sarcoid lungs.…”

Section: Discussionsupporting

confidence: 53%

“…To address the role for T-bet in sarcoidosis from this aspect, we studied its relationship with selected cytokines/receptors implicated in disease pathogenesis. Of the studied chemokine receptors, we observed a strong correlation between T-bet and CXCR6, a receptor co-expressed on CXCR3 T-cells in sarcoidosis [4]. Furthermore, a strong correlation was observed between T-bet and CCL5 and CXCL10, two chemokines that play an important role in the recruitment of T-cells to the sarcoid lungs [4,[15][16][17]19].…”

Section: Discussionmentioning

confidence: 99%

“…A key role in granuloma formation is played by interferon (IFN)-c [3] and Thelper (Th) type-1 cells accumulating in the sarcoid lungs, which express chemokine receptor CXC chemokine receptor (CXCR)3 [4]. There is evidence that both CXCR3 and IFN-c are under the direct control of a Th1 transcription factor, T-bet (T-box, expressed in T-cells) [5][6][7].…”

mentioning

confidence: 99%

“…To address the role for T-bet as a plausible regulator of immune mediators in sarcoidosis, we studied its relationship with cytokines and their receptors that have been previously implicated in the pathogenesis of sarcoidosis. Of these ''sarcoidosis-associated'' genes we mainly focused on chemokines directing the trafficking of activated T-cells into sarcoid lungs, such as CCL2, CCL5, CXCL9, CXCL10 and CXCL11 [14][15][16][17][18][19], and chemokine receptors, CC chemokine ligand (CCR)5 [10] and CXCR6 [4] preferentially expressed on activated lymphocytes.…”

mentioning

confidence: 99%

“…Secondly, we aimed to address the question as to whether there is evidence supporting the theory of T-bet modulation of CXCR3 and IFN-c gene expression in sarcoid lungs by performing correlation analyses of their mRNA expression profiles in BAL cells. Finally, we investigated the relationship of T-bet with a range of sarcoidosis-associated genes, namely: 1) ligands of CXCR3 receptor (CXCL9, CXCL10 and CXCL11) [14][15][16][17]; 2) chemokines CCL2 and CCL5 [18,19]; 3) chemokine receptors CCR2, CCR5 and CXCR6 [4,10,20,21]; and 4) b-chain subunit of IL-2R and IL-15R receptors [10,22]. Herein, we report upregulation of T-bet in sarcoidosis and its relationship with some sarcoid-associated molecules.…”

mentioning

confidence: 99%

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T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis

Kriegová¹,

Fillerová²,

Tománková³

et al. 2011

Eur Respir J

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Upregulation of genes for interferon (IFN)-γ and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T-bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with “sarcoidosis-associated” genes.Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry.Patient’s BAL cells expressed higher mRNA T-bet levels than those of controls (mean±sdfold change 3.64±1.72; p=0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Löfgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p>0.05). T-bet mRNA expression correlated with expression of IFN-γ, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor β, CXCR3 and CXCR6 (p<0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes.In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-γ, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis-associated genes.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis

Kriegová¹,

Fillerová²,

Tománková³

et al. 2011

Eur Respir J

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Inflammatory and oxidative stress biomarkers induced by silica exposure in crystal craftsmen

Carneiro

Algranti

Chérot‐Kornobis

et al. 2020

American J Industrial Med

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Background Identification of biomarkers associated with the diagnosis and prognosis of silicosis would be highly advantageous in the clinical setting. The aim of this study is to evaluate inflammatory and oxidative stress biomarkers in subjects exposed to silica. Methods A cross‐sectional study of crystal craftsmen currently (n = 34) or formerly (n = 35) exposed and a group of nonexposed subjects (n = 12) was performed. Personal respirable dust samples were collected. Plasma inflammatory mediators (bone morphogenetic protein‐ BMP2 and chemokines CXCL16, and CCL5), oxidative stress enzymes (thiobarbituric acid reactive substances [TBARs] and superoxide dismutase [SOD]), and nitrite (NO2−) were analyzed in parallel with nitric oxide in exhaled breath (FeNO). Results Being currently or formerly exposed to silica was related to increased levels of CXCL16 and TBARs. Currently, exposed subjects showed decreased levels of SOD. Thirty‐seven craftsmen with silicosis (26 formerly and 11 currently exposed) showed higher levels of CXCL16, which was positively associated with the radiological severity of silicosis. Compared with the nonexposed, subjects with silicosis had higher levels of TBARs and those with complicated silicosis had lower levels of SOD. In multivariate analysis, higher levels of CXCL16 were associated with exposure status and radiological severity of silicosis. Smoking was not a confounder. FeNO did not distinguish between the exposure status and the presence of silicosis. Conclusion CXCL16 emerged as a potential biomarker that could distinguish both silica exposure and silicosis. TBARs were elevated in exposed individuals. However, their clinical applications demand further investigation in follow‐up studies of representative samples.

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IL‐18 enhances IFN‐γ‐induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes

et al. 2007

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IL-18 is involved in the pathogenesis of atopic dermatitis, psoriasis, and allergic contact dermatitis. CXCL9, CXCL10, and CXCL11 recruit type 1 T cells, and the production of these chemokines by keratinocytes is enhanced in these dermatoses. We examined the in vitro effects of IL-18 on IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in human keratinocytes. IL-18 enhanced the IFN-gamma-induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of NF-kappaB, STAT1, and IFN-regulatory factor (IRF)-1. Antisense oligonucleotides against NF-kappaB p50, p65, or STAT1 suppressed CXCL9, CXCL10, and CXCL11 production, and antisense IRF-1 suppressed CXCL11 production. Inhibitors of PI3 K, p38 MAPK, and MEK suppressed IL-18 plus IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production and NF-kappaB, STAT1, and IRF-1 activities. IL-18 induced phosphorylation of ERK and Akt, while IFN-gamma induced phosphorylation of p38 MAPK. These results suggest that IL-18 may potentiate IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in keratinocytes by activating NF-kappaB, STAT1, or IRF-1 through PI3 K/Akt and MEK/ERK pathways. These effects of IL-18 may promote the infiltration of type 1 T cells into lesions with inflammatory dermatoses and amplify the skin inflammation. IL-18 may act as a pro-inflammatory cytokine in these dermatoses and thus is a candidate therapeutic target.

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Role for CXCR6 and Its Ligand CXCL16 in the Pathogenesis of T-Cell Alveolitis in Sarcoidosis

Abstract: T cells coexpressing CXCR3 and CXCR6 act coordinately with respective ligands and Th1 inflammatory cytokines in the alveolitic/granuloma phases of the disease.

Cited by 83 publications

References 28 publications

T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis

T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis

Inflammatory and oxidative stress biomarkers induced by silica exposure in crystal craftsmen

IL‐18 enhances IFN‐γ‐induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes

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