IL-17 and neutrophils: unexpected players in the type 2 immune response

Allen, Judith E.; Sutherland, Tara E.; Rückerl, Dominik

doi:10.1016/j.coi.2015.03.001

Cited by 73 publications

(56 citation statements)

References 88 publications

(107 reference statements)

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“…These data implicate another potential source of IL-17, which seems to be dominant during the acute response to P. aeruginosa in the CF mouse lung, consistent with the findings of other studies (20,21,43) and a study from our group recently accepted for publication (32).…”

Section: Rag1supporting

confidence: 80%

“…Increased concentrations of IL-17 have been associated with a wide range of inflammatory diseases, including rheumatoid arthritis (15,16), inflammatory bowel disease (17), diabetes (18,19), cancer (20), and allergic asthma (21,22). The utilization of neutralizing IL-17A antibodies in a mouse model of allergic asthma (23,24) and lipopolysaccharide-induced inflammation (9,25) demonstrated decreased airway neutrophilia, implicating IL-17 as a potential therapeutic target in asthma.…”

mentioning

confidence: 99%

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Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

et al. 2016

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c Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated with Pseudomonas aeruginosa colonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17. Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected with P. aeruginosa had robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed with P. aeruginosa infection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency of Cftr and ongoing inflammation. These studies demonstrate the in vivo contribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis. Cystic fibrosis (CF) lung disease is characterized by an exaggerated inflammatory response associated with the robust infiltration of neutrophils within the airways (1, 2). The etiology of this excessive inflammation remains to be elucidated. Many cytokines and small molecules have been shown to recruit neutrophils into the airway of individuals with CF, including interleukin-8 (IL-8) and leukotriene (LT) B4 (3-7). IL-17 has traditionally been identified to be a product of activated T lymphocytes and is critically important in the host lung response to infections caused by Gram-negative bacteria, including Pseudomonas aeruginosa (8,9). Experiments with IL-17 receptor knockout (KO) mice have demonstrated an increased susceptibility to Gram-negative bacterial pneumonia due to excessive neutrophil recruitment into the airways (10-13) and the upregulation of airway mucins, potentially contributing to inefficient mucociliary clearance (5,14).Increased concentrations of IL-17 have been associated with a wide range of inflammatory diseases, including rheumatoid arthritis (15, 16), inflammatory bowel disease (17), diabetes (18,19), cancer (20), and allergic asthma (21, 22). The utilization of neutralizing IL-17A antibodies in a mouse model of allergic asthma (23, 24) and lipopolysaccharide-induced inflammation (9, 25) demonstrated decreased airway neutrophilia, implicating IL-17 as a potential therapeutic target in asthma. IL-17 has also been associated with P. aeruginosa infections, linking it to not just the patholo...

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Section: Rag1supporting

confidence: 80%

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confidence: 99%

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

et al. 2016

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“…Interestingly, neutrophil infiltration into the TC was comparable between infected IL-17A-deficient mice and WT control groups even though IL-17A was previously shown to be important for the recruitment and activation of neutrophils through the induction of a variety of cytokines and chemokines during lung inflammation (Allen et al 2015). Although the eosinophil recruiting chemokine eotaxin-1 was significantly reduced in the TC of infected IL-17A −/− mice, the number of eosinophils in the TC was comparable between IL-17A −/− and WT groups.…”

Section: Discussionmentioning

confidence: 87%

“…This suggests that L. sigmodontis -driven recruitment of neutrophils and eosinophils into the TC is independent of IL-17A secretion but may affect their functional responses. Potentially, the lack of IL-17A and reduced eotaxin-1 levels in the TC can be compensated through other neutrophil or eosinophil recruitment/activation chemokines like CXCL1, CXCL5 and CXCL8 (Allen et al 2015) or MCP-5, MIP-1α, CXCL9, CXCL10, CXCL12 and RANTES (Simon et al 2004), respectively. Indeed, RANTES levels were increased (not significantly) in a couple of IL-17A −/− mice when compared to WT controls.…”

Section: Discussionmentioning

confidence: 99%

Absence of IL-17A in Litomosoides sigmodontis-infected mice influences worm development and drives elevated filarial-specific IFN-γ

et al. 2018

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Lymphatic filariasis, onchocerciasis and loiasis are widespread neglected tropical diseases causing serious public health problems and impacting the socio-economic climate in endemic communities. More than 100 million people currently suffer from filarial infections but disease-related symptoms and infection-induced immune mechanisms are still ambiguous. Although most infected individuals have dominant Th2 and regulatory immune responses leading to a homeostatic regulated state, filarial-induced overt pathology like lymphedema, dermal pathologies or blindness can occur. Interestingly, besides dominant Th2 and regulatory T cell activation, increased Th17-induced immune responses were associated with filarial infection and overt helminth-induced pathology in humans. However, the immunological mechanisms of Th17 cells and the release of IL-17A during filarial infections remain unclear. To decipher the role of IL-17A during filarial infection, we naturally infected IL-17A−/− and wildtype C57BL/6 mice with the rodent filariae Litomosoides sigmodontis and analysed parasite development and immune alterations. Our study reveals that infected IL-17A-deficient C57BL/6 mice present reduced worm burden on days 7 and 28 p.i. but had longer adult worms on day 28 p.i. in the thoracic cavity (TC), the site of infection. In addition, infiltration of CD4+ T cells, CD4+Foxp3+ regulatory T and functional CD4+Rorγt+pStat3+ Th17 cells in the TC was reduced in IL-17A-deficient mice accompanied by reduced eotaxin-1 and CCL17 levels. Furthermore, mediastinal lymph node cells isolated from IL-17A−/− mice showed increased filarial-specific IFN-γ but not IL-4, IL-6, or IL-21 secretion. This study shows that Th17 signalling is important for host immune responses against filarial infection but appears to facilitate worm growth in those that reach the TC.Electronic supplementary materialThe online version of this article (10.1007/s00436-018-5959-7) contains supplementary material, which is available to authorized users.

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“…b Correlation analyses between the levels of CXCL10 and other chemokines in ueRA patients (Spearman rank correlation test; r). *P ≤ 0.05, *** P ≤ 0.001, **** P ≤ 0.0001 activation and, according to recent models, Th2 and Th17 pathways may amplify each other in certain conditions [30]. Thus, the dominance of Th2 and Th17 milieu may induce a granulocyte-mediated type I IFN response, which may further induce downstream secretion of CXCL10 and other chemokines contributing to early RA pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

08.07 Blood chemokine profile in untreated early rheumatoid arthritis: cxcl10 as a disease activity marker

Pandya

Lundell

Andersson

et al. 2017

Autoimmune Inflammation

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Background: We have recently analyzed the profile of T-cell subtypes based on chemokine receptor expression in blood from untreated early rheumatoid arthritis (ueRA) patients compared to healthy controls (HC). Here, we compared the levels of the respective chemokines in blood plasma of ueRA patients with those of HC. We also studied the association of chemokine levels with the proportions of circulating T-cell subsets and the clinical disease activity. Methods: Peripheral blood was obtained from 43 patients with ueRA satisfying the ACR 2010 criteria and who had not received any disease-modifying anti-rheumatic drugs (DMARD) or prednisolone, and from 14 sex-and age-matched HC. Proportions of T helper cells in blood, including Th0, Th1, Th2, Th17, Th1Th17, TFh, and regulatory T cells, were defined by flow cytometry. Fifteen chemokines, including several CXCL and CCL chemokines related to the T-cell subtypes as well as to other major immune cells, were measured in blood plasma using flow cytometry bead-based immunoassay or ELISA. Clinical disease activity in patients was evaluated by assessing the following parameters: Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), swollen joint counts (SJC), tender joint counts (TJC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The data were analyzed using multivariate factor analyses followed by univariate analyses. Results: Multivariate discriminant analysis showed that patients with ueRA were separated from HC based on the blood plasma chemokine profile. The best discriminators were CXCL9, CXCL10, CXCL13, CCL4, and CCL22, which were significantly higher in ueRA compared to HC in univariate analyses. Among the chemokines analyzed, only CXCL10 correlated with multiple disease activity measures, including DAS28-CRP, DAS28-ESR, CDAI, SJC in 66 joints, CRP, and ESR.Conclusions: High circulating levels of CXCL10 in the plasma of ueRA patients and the association with the clinical disease activity suggests that CXCL10 may serve as a disease activity marker in early rheumatoid arthritis.

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IL-17 and neutrophils: unexpected players in the type 2 immune response

Cited by 73 publications

References 88 publications

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

Absence of IL-17A in Litomosoides sigmodontis-infected mice influences worm development and drives elevated filarial-specific IFN-γ

08.07 Blood chemokine profile in untreated early rheumatoid arthritis: cxcl10 as a disease activity marker

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