Pleiotropic Immune Functions of Chemokine Receptor 6 in Health and Disease

Ranasinghe, Ranmali; Eri, Rajaraman

doi:10.20944/preprints201806.0107.v1

Cited by 10 publications

(14 citation statements)

References 51 publications

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“…Although the literature is rich in defining the immunosuppressive role of cigarette smoke exposure on TCR-reactivated antigen-specific Th cells 3 , its effect on memory resting Th cells in a quiescent state is not known. Through the study of peripheral CCR6 + Th17 cells 26 exposed to cigarette smoke independently of TCR stimulation, we provide evidences that higher sensitivity to CSE-induced premature senescence of resting CCR6 + Th17 cells compared to other memory CD4 + T cells relies on higher basal ROS production and dependent signalling in these cells. Moreover, CSE-induced premature senescence of CCR6 + Th17 is associated with VEGFα production, which could confer pathogenicity to CCR6 + Th17 cells and contribute to worsen chronic inflammation in smokers with autoimmune diseases when homing to mucosal tissues.…”

Section: Discussionmentioning

confidence: 86%

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion

Baskara

Kerbrat

Dagouassat

et al. 2020

Sci Rep

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Chronic exposure to environmental pollutants is often associated with systemic inflammation. As such, cigarette smoking contributes to inflammation and lung diseases by inducing senescence of pulmonary cells such as pneumocytes, fibroblasts, and endothelial cells. Yet, how smoking worsens evolution of chronic inflammatory disorders associated with Th17 lymphocytes, such as rheumatoid arthritis, psoriasis, Crohn's disease, and multiple sclerosis, is largely unknown. Results from human studies show an increase in inflammatory CD4 + Th17 lymphocytes at blood-and pulmonary level in smokers. The aim of the study was to evaluate the sensitivity of CD4 + Th17 lymphocytes to cigarette smoke-induced senescence. Mucosa-homing CCR6 + Th17-were compared to CCR6 neg -and regulatory T peripheral lymphocytes after exposure to cigarette smoke extract (CSE). Senescence sensitivity of CSE-exposed cells was assessed by determination of various senescence biomarkers (β-galactosidase activity, p16 Ink4a -and p21 expression) and cytokines production. CCR6 + Th17 cells showed a higher sensitivity to CSE-induced senescence compared to controls, which is associated to oxidative stress and higher VeGfα secretion. Pharmacological targeting of ROS-and ERK1/2 signalling pathways prevented CSEinduced senescence of CCR6 + Th17 lymphocytes as well as VEGFα secretion. Altogether, these results identify mechanisms by which pro-oxidant environmental pollutants contribute to pro-angiogenic and pathogenic CCR6 + Th17 cells, therefore potential targets for therapeutic purposes.open Scientific RepoRtS | (2020) 10:6488 | https://doi.Statistical analysis. The sample sizes were dependent on the experimental question and are shown in the related figures. 32 individual healthy donors were studied for all experiments shown in this manuscript. At least, 4individual healthy donors were used for the study of each marker of senescence. Each donor was used to test two different biomarkers at least, depending on the yield of T cells sorting. Statistical analysis tests were performed using Prism version 5.04 (GraphPad, La Jolla, CA, USA) and data are represented as mean standard error of the mean (SEM). As the gaussian distribution of the different biomarkers could not be checked, non-parametric tests were used to address their statistical relevance. The Mann-Whitney test was used to compare the means of two groups of ordinal (non-parametric) data, and the Kruskal-Wallis test (non-parametric test) was used to compare between the 3 groups.

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Section: Discussionmentioning

confidence: 86%

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion

Baskara

Kerbrat

Dagouassat

et al. 2020

Sci Rep

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“…Biochemically, chemokines are small proteins consisting of lower molecular weights within 8-14 kilo Daltons. Biological activities of chemokines are numerous, which include, embryogenesis, wound healing, development of vasculature, T lymphocyte development and differentiation, leukocyte homeostasis, B cell development and maturation [9][10][11][12].…”

Section: Chemokines -Chemokine Receptor 6 (Ccr6) and CC -Chemokine Limentioning

confidence: 99%

“…Contrary to the earlier belief of TH1/TH2 dual immune activation pathways in understanding IBD, the recent hypothesis which attracted more attention has been to deeply evaluate the TH17-Treg dysfunction, of which the immune-driven cues and inherent mechanisms still remain obscure. TH17 cells are associated with an inflammatory phenotype whereas the regulatory Treg cells are linked to an anti-inflammatory suppressive role [9][10][11][12].…”

Section: Chemokines -Chemokine Receptor 6 (Ccr6) and CC -Chemokine Limentioning

confidence: 99%

“…CCR6 expression on regulatory Treg cells are induced by TGF-β and IL-10 together with the nuclear receptor forkhead box P3 (FoxP3). Interestingly, there is evidence obtained from the experimental models where both TH17 and Treg cells being able to oscillate between both inflammatory and suppressive roles [9][10][11][12]. Therefore, it is immensely important to be able to identify the immune ingredients which tilt this precarious immune imbalance towards a cure pathway.…”

Section: Chemokines -Chemokine Receptor 6 (Ccr6) and CC -Chemokine Limentioning

confidence: 99%

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CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

Ranasinghe¹,

Eri²

2018

Preprint

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Inflammatory bowel disease (IBD) is a CC chemokine receptor 6 (CCR6) -associated immune mediated disorder which has attracted an extensive superfluity of experimental analyses. IBD has come to the fore of varied scrutinizing owing to its complexity by nature for comprising of two synergistic sub phenotypes; Crohn's disease (CD) and Ulcerative colitis (UC). Both these disease entities cause potent immune dysregulation followed by intense tissue damage within the gut mucosal system, initiating symptoms which are severely debilitating. Multiple causative factors are said to be responsible for IBD but direct immune dysfunction is kindled by overplay of innate and adaptive immune responses produced against a pathogenic microbial attack through the weakened or leaky gut epithelial barrier. Once immune homeostasis is not achieved by tolerating agents, the self-assertive adaptive immunity mobilize its various T and B cell cohorts initializing their allied immune mechanisms by vigorously deploying them towards the site of infection. CCR6 and its unique solitary ligand CC-chemokine ligand 20 (CCL20) are small protein molecules which are abundantly expressed by T and B lymphocytes and act as chemotactic immune-modulatory envoys that help in the deployment of the effector lymphocyte arm of the immune system, producing two directly opposing outcomes in IBD. This dichotomous immunity consists of either immune tolerance or inflammation which then develops into a chronic state, remaining catatonic to inherent immunity or targeted clinical therapy. In this review, we have chronologically identified a plethora of experimental studies radiating into 14 different compartments highlighted in the visual depiction which have employed both mouse models and clinical subjects spanning a period of nearly two decades. In doing so, we expect the research community would further benefit by tracing through the history, thereby understanding the CCR6 -CCL20 axis in IBD and identifying the gaps in literature which can be fortuitously filled in the future.Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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“…Chemokines play a prominent role in inflammation and spreading of cancer and interestingly, chemokine inhibition has yielded anti-inflammatory attributes in inflammatory disorders [1].…”

Section: Chemokinesmentioning

confidence: 99%

CCR6-CCL20 Signalling Networks in Inflammatory Bowel Disease

Ranasinghe¹,

Eri²

2018

Preprint

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Inflammatory bowel disease (IBD) has evoked a significant interest in human immunobiology given its tactical immune evasion methodologies resulting in acute immune destabilization. IBD comprising of Crohn’s disease and Ulcerative colitis manifest as chronic inflammation in the gut mucosa, leading to complexities involving immune dysregulation in the T helper lymphocyte arm effecting disease pathogenicity. The mucosa of the alimentary canal is constantly exposed to a myriad of food antigens and luminal microorganisms for which a consistent host-protective mechanism is operative in healthy people. Lowered mucosal immune expression which allows penetration of the epithelial barrier by infective pathogenic microbes, elicits both innate and adaptive immune responses in the gut culminating in aberrant intestinal inflammation. Interestingly, IBD leukocyte repertoire is significantly entwined with chemokine assisted chemotactic navigation into the sites of inflammation which is also thought to generate favourable immune suppressive responses. The functions of the cognate chemokine receptor, CCR6, which binds with its unique ligand CCL20, are expected to tilt the balance between upregulation of homeostatic tolerance and inflammatory pathophysiology. This review aims at critically examining the CCR6 driven immune pathways; TH1/TH2, TH1/TH17, TH17/ Treg, IL-23/IL-17, Akt/ERK-1 /2, ILC3 for systematic investigation of its underlying mechanisms in the future and to underpin its importance in resolving IBD aetiopathology. Thus, CCR6 occupies an exclusive position in gut immunology which renders it an invaluable therapeutic tool for the production of novel medicaments to treat IBD.

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Pleiotropic Immune Functions of Chemokine Receptor 6 in Health and Disease

Cited by 10 publications

References 51 publications

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion

CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

CCR6-CCL20 Signalling Networks in Inflammatory Bowel Disease

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