In Vivo Induction of Cutaneous Inflammation Results in the Accumulation of Extracellular Trap-Forming Neutrophils Expressing RORγt and IL-17

Keijsers, R.R.M.C.; Hendriks, A.G.M.; Erp, P.E.J. van; Cranenbroek, Bram van; Kerkhof, Peter C M van de; Koenen, Hans J. P. M.; Joosten, Irma

doi:10.1038/jid.2013.526

Cited by 107 publications

(97 citation statements)

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“…Neutrophils are a source of IL17 in human psoriatic lesions and in several mouse models of infectious and autoimmune inflammation (17,18). Elevated IL17 expression has also been observed in patients with corneal ulcers caused by filamentous fungi; neutrophils are the predominant infiltrating cells in these ulcers (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-17–Producing Neutrophils Link Inflammatory Stimuli to Disease Progression by Promoting Angiogenesis in Gastric Cancer

Jiang

et al. 2017

Clinical Cancer Research

125

134

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Purpose: Elevated levels of neutrophils have been associated with poor survival in various cancers, but direct evidence supporting a role for neutrophils in the immunopathogenesis of human cancers is lacking.Experimental Design: A total of 573 patients with gastric cancer were enrolled in this study. Immunohistochemistry and real-time PCR were performed to analyze the distribution and clinical relevance of neutrophils in different microanatomic regions. The regulation and function of neutrophils were assessed both in vitro and in vivo.Results: Increased neutrophil counts in the peripheral blood were associated with poor prognosis in gastric cancer patients. In gastric cancer tissues, neutrophils were enriched predominantly in the invasive margin, and neutrophil levels were a powerful predictor of poor survival in patients with gastric cancer. IL17 þ neutrophils constitute a large portion of IL17-producing cells in human gastric cancer. Proinflammatory IL17 is a critical mediator of the recruitment of neutrophils into the invasive margin by CXC chemokines. Moreover, neutrophils at the invasive margin were a major source of matrix metalloproteinase-9, a secreted protein that stimulates proangiogenic activity in gastric cancer cells. Accordingly, high levels of infiltrated neutrophils at the invasive margin were positively correlated with angiogenesis progression in patients with gastric cancer.Conclusions: These data provide direct evidence supporting the pivotal role of neutrophils in gastric cancer progression and reveal a novel immune escape mechanism involving fine-tuned collaborative action between cancer cells and immune cells in the distinct tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

Interleukin-17–Producing Neutrophils Link Inflammatory Stimuli to Disease Progression by Promoting Angiogenesis in Gastric Cancer

Jiang

et al. 2017

Clinical Cancer Research

125

134

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“…In contrast, a recent study showed that neutrophils can produce IL-17, such as in the mouse kidney ischemia-reperfusion injury 29 or in in vivo models of skin inflammation with histological features of human psoriasis 30 . In agreement with the previous study 28 , we found that CD8 + T cells, but not neutrophils, mainly produced IL-17A in skin dLNs at 18 h and 5 days post-sensitization with DNFB (supplementary Fig.…”

Section: Suppression Of Chs With Impaired Sensitization In Aqp9mentioning

confidence: 92%

Aquaporin-9-expressing neutrophils are required for the establishment of contact hypersensitivity

Moniaga

Hara‐Chikuma

2016

Journal of Dermatological Science

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1Aquaporin-9 (AQP9), a water/glycerol channel protein, is expressed in several immune cells including neutrophils; however, its role in immune response remains unknown. Here we show the involvement of AQP9 in hapten-induced contact hypersensitivity (CHS), as a murine model of skin allergic contact dermatitis, using AQP9 knockout (AQP9 −/− ) mice. First, the CHS response to hapten dinitrofluorobenzene (DNFB) was impaired in AQP9 −/− mice compared with wild-type (WT) mice. Adoptive transfer of sensitized AQP9 −/− draining lymph node (dLN) cells into WT recipients resulted in a reduced CHS response, indicating impaired sensitization in AQP9 −/− mice. Second, administration of WT neutrophils into AQP9 −/− mice during sensitization rescued the impaired CHS response. Neutrophil recruitment to dLNs upon hapten application was attenuated by AQP9 deficiency. Coincidentally, AQP9 −/− neutrophils showed a reduced CC-chemokine receptor 7 (CCR7) ligand-induced migration efficacy, which was attributed to the attenuated recruitment of neutrophils to dLNs. Furthermore, we found that neutrophil deficiency, observed in AQP9 −/− or neutrophildepleted mice, decreased IL-17A production by dLN cells, which might be responsible for T cell activation during a subsequent CHS response. Taken together, these findings suggest that AQP9 is required for the development of sensitization during cutaneous acquired immune responses via regulating neutrophil function.Allergic contact dermatitis (ACD) is one of the most prevalent skin diseases consisting of sensitization and elicitation phases 1,2 . Advanced studies of hapten-induced contact hypersensitivity (CHS) as a murine model of ACD have expanded our understanding of the mechanism of allergic reactions occurring in the skin, especially the specific roles of a variety of immune cells. During the sensitization phase, hapten-bearing cutaneous dendritic cells (DCs) migrate into skin draining lymph nodes (dLNs), where the presentation of antigens to naïve T cells and subsequent T cell priming occur. During the elicitation phase, re-exposure to cognate hapten results in the recruitment of antigen-specific T cells to the site of allergen challenge and T cell-mediated tissue damage 2 . Increasing evidence shows that several subsets of immune cells, including various types of T cells (Th1, Th17, regulatory, and natural killer), DCs (dermal DCs and Langerhans cells), and mast cells, work synergistically in the skin and its dLNs to exert antigen presentation and T cell activation during the development of sensitization in CHS [3][4][5][6][7] . Neutrophils have long been considered as the final effector cells of an acute inflammatory response. On the other hand, accumulating evidence has extended the function of neutrophils to include activation and regulation during innate and adaptive immune responses 8,9 . Several studies have focused on the

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“…This is also the case following in vivo induction of cutaneous inflammation in humans following topical application of leukotriene B4 (LTB4) or tape stripping [69]. However, since T cells tend to release rather than store their cytokines, it can be difficult to identify T cell cytokines using immunohistochemistry.…”

Section: What Is the Primary Source Of Il-17 In Pso And Psa?mentioning

confidence: 99%

“…An example of this limitation is a study in which very few IL-17+ T cells were identified on immunohistochemical analysis of psoriatic skin biopsies but flow cytometric analysis of T cells isolated from the skin revealed abundant IL-17+ T cells [50]. Nonetheless, neutrophils expressing RORγt and IL-17 mRNA are enriched in inflamed compared to normal skin, and in the LTB4 model of skin inflammation, the influx of neutrophils precedes the influx of T cells [69]. IL-17+ mast cells are present in both psoriatic and normal skin and in the synovium of patients with PsA [50,69,70].…”

Section: What Is the Primary Source Of Il-17 In Pso And Psa?mentioning

confidence: 99%

Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

2015

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Investigators have accrued compelling evidence that the IL-17 pathway is central to the pathogenesis of psoriasis and psoriatic arthritis. The evidence comprises genome-wide association studies (GWAS), data from experimental murine models and findings from in vitro studies on patients' cells or tissue biopsies. More recently, the success of drugs blocking the IL-17 pathway in treating both psoriasis (PsO) and psoriatic arthritis (PsA) confirms that IL-17 is a clinically relevant therapeutic target. However, there remain many unanswered questions: is PsA simply an extension of PsO from the skin to the synovial tissue or are there differences in the underlying pathogenesis of these diseases? Which cell type represents the primary source of IL-17 in PsO and PsA? And how are these cells regulated? This review outlines the IL-17 pathway, summarises the evidence supporting its role in PsO and PsA and discusses recent data that may help to address these yet unresolved questions.

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In Vivo Induction of Cutaneous Inflammation Results in the Accumulation of Extracellular Trap-Forming Neutrophils Expressing RORγt and IL-17

Cited by 107 publications

References 39 publications

Interleukin-17–Producing Neutrophils Link Inflammatory Stimuli to Disease Progression by Promoting Angiogenesis in Gastric Cancer

Interleukin-17–Producing Neutrophils Link Inflammatory Stimuli to Disease Progression by Promoting Angiogenesis in Gastric Cancer

Aquaporin-9-expressing neutrophils are required for the establishment of contact hypersensitivity

Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

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