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

Abstract

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.

Role of Smoking in the Pathogenesis of Multiple Sclerosis: A Review Article

“…It has been reported that free radical-induced oxidative stress causes mutations in genetic material and is involved in several neurodegenerative disorders, such as Parkinson's disease and MS. Tobacco increases the risk of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, and is associated with other autoimmune disorders like MS [11,12]. Cigarette smoke acts on the cellular level of the immune system, resulting in the development of proinflammatory cytokines [11][12][13]. Smokers have high levels of proinflammatory cytokines (e.g., IL-6), higher levels of C-reactive protein, fibrinogen, and other inflammatory markers [11].…”

“…Current cigarette smokers had more severe disease at baseline than never-smokers in terms of Expanded Disability Status Scale score (EDSS) [37]. Exposure to pollutants present in tobacco-related products contributes to the development of proangiogenic and pathogenic CCR6 + Th17 cells [12]. These cells worsen chronic inflammatory disorders, such as MS and rheumatoid arthritis [12].…”

“…Exposure to pollutants present in tobacco-related products contributes to the development of proangiogenic and pathogenic CCR6 + Th17 cells [12]. These cells worsen chronic inflammatory disorders, such as MS and rheumatoid arthritis [12]. Di Pauli et al study reported that nicotine users diagnosed with the CIS develop a clinically definite course of the disease (CDMS) in a shorter period than non-smokers [42].…”

Some Molecular and Cellular Stress Mechanisms Associated with Neurodegenerative Diseases and Atherosclerosis

“…In addition, telomere shortening and senescence associated with factors such as epigenomic damage, strong mitogen–associated signals and activation of tumor suppressors [ 194 , 202 ]. Smoking and unfavorable environmental factors worsen senescence and the ageing of the whole organism [ 194 , 203 , 204 ]. Moreover, these processes are often linked with chronic stress, diabetes, hypertension, coronary heart disease and other age-related diseases [ 194 , 205 ].…”

Senescence in Pulmonary Fibrosis: Between Aging and Exposure

“…Chronic inflammation induced by particulate matter exposure triggers T cell senescence, with external stimuli or neighboring senescent cells producing an inflammatory microenvironment (SASP) that reprograms the metabolic machinery of CD8 + T cells by boosting mitochondrial biogenesis, and thus ROS production, distinctively defined as inflamm-aging (339). Cigarette smoke from human studies show an increase in inflammatory CD4+ Th17 lymphocytes at blood-and pulmonary level in smokers (340,341).…”