Th17/Treg Imbalance in Murine Cystic Fibrosis Is Linked to Indoleamine 2,3-Dioxygenase Deficiency but Corrected by Kynurenines

Iannitti, Rossana Giulietta; Carvalho, Agostinho; Cunha, Cristina; Luca, Antonella De; Giovannini, Gloria; Casagrande, Andrea; Zelante, Teresa; Vacca, Carmine; Fallarino, Francesca; Puccetti, Paolo; Massi-Benedetti, Cristina; Defilippi, G.; Russo, Maria Chiara; Porcaro, Luigi; Colombo, Carla; Ratclif, Luigi; Benedictis, Fernando Maria de; Romani, Luigina

doi:10.1164/rccm.201207-1346oc

Cited by 89 publications

(79 citation statements)

References 66 publications

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“…The balance between T-helper (Th)17 cells and Tregs is closely linked to inflammation and tolerance in the intestine [41]. As the Th17 pathway primarily evokes a neutrophil response, this is particularly interesting in the context of the prevalent neutrophilia found in cystic fibrosis lung disease [18,42]. Given the similarities of the mucosal environments of the gut and the lungs, it will be important to investigate whether SCFAs can modulate the Th17/Treg axis in the cystic fibrosis airways [43].…”

Section: Discussionmentioning

confidence: 99%

Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth

et al. 2015

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The hypoxic environment of cystic fibrosis airways allows the persistence of facultative anaerobic bacteria, which can produce short-chain fatty acids (SCFAs) through fermentation. However, the relevance of SCFAs in cystic fibrosis lung disease is unknown. We show that SCFAs are present in sputum samples from cystic fibrosis patients in millimolar concentrations (mean±SEM 1.99±0.36 mM).SCFAs positively correlated with sputum neutrophil count and higher SCFAs were predictive for impaired nitric oxide production. We studied the effects of the SCFAs acetate, propionate and butyrate on airway inflammatory responses using epithelial cell lines and primary cell cultures. SCFAs in concentrations present in cystic fibrosis airways (0.5-2.5 mM) affected the release of granulocytemacrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin (IL)-6. SCFAs also resulted in higher IL-8 release from stimulated cystic fibrosis transmembrane conductance regulator (CFTR) F508del-mutant compared to wild-type CFTR-corrected bronchial epithelial cells. At 25 mM propionate reduced IL-8 release in control but not primary cystic fibrosis epithelial cells. Low (0.5-2.5 mM) SCFA concentrations increased, while high (25-50 mM) concentrations decreased inducible nitric oxide synthase expression. In addition, SCFAs affected the growth of Pseudomonas aeruginosa in a concentration-and pH-dependent manner.Thus, our data suggest that SCFAs contribute to cystic fibrosis-specific alterations of responses to airway infection and inflammation. @ERSpublications Short-chain fatty acids contribute to CF-specific alterations of responses to airway infection and inflammation

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Section: Discussionmentioning

confidence: 99%

Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth

et al. 2015

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“…An imbalance between pro-and anti-inflammatory signals may prevent successful host/ fungal interaction, thus leading to infection and disease. Indeed, despite the occurrence of severe aspergillosis in immunocompromised patients, clinical evidence indicates that aspergillosis also occurs in the setting of a heightened inflammatory response, such as in nonneutropenic patients after allogeneic hematopoietic stem cell transplantation (HSCT) (35), in chronic granulomatous disease (36), and in cystic fibrosis (37). Therefore, paradoxically, increased in- flammatory innate response may predispose to either fungal infections or dysregulated immune responses to the fungus.…”

Section: Discussionmentioning

confidence: 99%

PTX3 Binds MD-2 and Promotes TRIF-Dependent Immune Protection in Aspergillosis

Bozza

Campo

Arseni

et al. 2014

The Journal of Immunology

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The long pentraxin 3 (PTX3) modulates different effector pathways involved in innate resistance to Aspergillus fumigatus, including complement activation or promotion of phagocytosis by interacting with FcγRs. However, whether and how TLRs modulate PTX3 mediates antifungal resistance is not known. In this study, we demonstrate that PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts its protective antifungal activity in vivo through TLR4/MD-2–mediated signaling. Similar to Tlr4−/− mice, Md2−/− mice displayed high susceptibility to pulmonary aspergillosis, a phenotype associated with a proinflammatory cytokine profile and impaired antifungal activity of polymorphonuclear neutrophils. Treating Md2−/− mice with PTX3 failed to confer immune protection against the fungus, whereas adoptive transfer of MD-2–competent polymorphonuclear neutrophils restored it. Mechanistically, engagement of MD-2 by PTX3-opsonized Aspergillus conidia activated the TLR4/Toll/IL-1R domain-containing adapter inducing IFN-β–dependent signaling pathway converging on IL-10. Thus, we have identified a novel receptor mechanism, involving the TLR4/MD-2/Toll/IL-1R domain-containing adapter inducing IFN-β–mediated signaling, whereby PTX3 elicits antifungal resistance with limited immunopathology in A. fumigatus infection.

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“…Importantly, T cells, the major orchestrators of adaptive immune responses exhibit abnormal function in CF patients, cells and mice [58]. A series of publications now supports the concept that CF T cells are skewed towards a Th2/Th17 immune response that is associated with or even primes for infection with P. aeruginosa [5,[83][84][85]. Overshooting T cell responses are counter-regulated by regulatory T cells (Tregs) and myeloidderived suppressor cells (MDSCs) and recent studies support the notion that MDSCs are enhanced [86], while Tregs are reduced [87] in CF with P. aeruginosa infections, but the underlying mechanisms and clinical implications remain to be defined.…”

Section: Calgranulinsmentioning

confidence: 99%

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

Cantin

Hartl

Konstan

et al. 2015

Journal of Cystic Fibrosis

389

322

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Lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Although CF lung disease is primarily an infectious disorder, the associated inflammation is both intense and ineffective at clearing pathogens. Persistent high-intensity inflammation leads to permanent structural damage of the CF airways and impaired lung function that eventually results in respiratory failure and death. Several defective inflammatory responses have been linked to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency including innate and acquired immunity dysregulation, cell membrane lipid abnormalities, various transcription factor signaling defects, as well as altered kinase and toll-like receptor responses. The inflammation of the CF lung is dominated by neutrophils that release oxidants and proteases, particularly elastase. Neutrophil elastase in the CF airway secretions precedes the appearance of bronchiectasis, and correlates with lung function deterioration and respiratory exacerbations. Anti-inflammatory therapies are therefore of particular interest for CF lung disease but must be carefully studied to avoid suppressing critical elements of the inflammatory response and thus worsening infection. This review examines the role of inflammation in the pathogenesis of CF lung disease, summarizes the results of past clinical trials and explores promising new anti-inflammatory options.

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Th17/Treg Imbalance in Murine Cystic Fibrosis Is Linked to Indoleamine 2,3-Dioxygenase Deficiency but Corrected by Kynurenines

Abstract: This study provides a link between tryptophan catabolism and lung immune homeostasis in murine CF, representing a proof-of-concept that targeting pathogenic inflammation via IDO-mimetic drugs may benefit patients with CF.

Cited by 89 publications

References 66 publications

Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth

Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth

PTX3 Binds MD-2 and Promotes TRIF-Dependent Immune Protection in Aspergillosis

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

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