Air Pollution as a Contributor to the Inflammatory Activity of Multiple Sclerosis

Abstract

OBJECTIVE Air pollution has been recently identified as a risk factor for multiple sclerosis. Aim of this study was to investigate the immunological mechanism underlying the clinical association between air pollution, namely exposure to particulate matter 10 (PM10), and inflammatory activity of multiple sclerosis (MS) METHODS Daily recording of PM10 was obtained by monitors depending on the residence of subjects. Expression of molecules involved in activation, adhesion and migration of T lymphocytes were tested by flow-cytometry in 57 MS patients. We next assessed in vitro the effect of PM10 on expression of C-C chemokine receptors 6 (CCR6) by peripheral blood mononuclear cells (PBMCs), on cytokine production by monocyte-derived dendritic cells (mdDC) and on T cell polarization in PBMC/mdDC mixed cultures. RESULTS We identified a significant correlation between mean PM10 levels and expression of CCR6 CD4 + T circulating cells in MS patients. This was paralleled by the observation in vitro of a higher level of CCR6 expression on PBMC following treatment with increased doses of particulate matter. Moreover, in mdDC cultures particulate matter induced the secretion by mdDC of Th17 polarizing IL1 beta, IL6 and IL23 and, in mdDC/PBMC mixed cultures, enhanced generation of IL17-producing T cells. CONCLUSIONS Ex vivo and in vitro studies support the pro-inflammatory role of PM in MS, by upregulating expression of CCR6 on circulating CD4 + T cells and inducing in innate immune cells the production of Th17 polarizing cytokines. Therefore, we speculate that in MS respiratory exposure to PM10 may induce the production in the lung of autoreactive Th17 lymphocytes and boost their migratory properties through the blood-brain barrier.

The effect of air pollution on COVID‐19 severity in a sample of patients with multiple sclerosis

“…This observation parallels previous evidence in experimental autoimmune encephalomyelitis, the animal model of MS, of a primary role of the lung in licensing auto‐reactive lymphocytes to enter the central nervous system by boosting their migratory properties [33]. PM could increase interleukin 1beta (IL1beta), IL6 and IL23 production by DCs and enhance DC‐dependent generation of IL17‐producing T cells [32]. Finally, air pollution might trigger epigenetic changes, especially DNA methylation alterations, resulting in pro‐inflammatory cytokine production [33].…”

“…This could occur through various mechanisms related not only to respiratory impairment but also to the inflammatory up‐stimulation leading to the dreaded cytokine storm syndrome [31]. Air pollutants inhaled in the lower respiratory tract may stimulate lung resident dendritic cells (DCs) and, after migration to bronchial associated lymphoid tissue, induce a pro‐inflammatory response with generation of Th17 cells and enhance their migratory properties, ultimately leading to inflammatory exacerbations [32]. This observation parallels previous evidence in experimental autoimmune encephalomyelitis, the animal model of MS, of a primary role of the lung in licensing auto‐reactive lymphocytes to enter the central nervous system by boosting their migratory properties [33].…”

Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease

“…Increased numbers of circulating myeloid DCs that express cytokines such as IL-1β, IL-6, and IL-23, which stimulate the development of Th17 cells, were reported in these patients. 286,296,299 Their findings were associated with an increase in CCR6 + CD4 + T cells with the migratory capacity to pass through the blood-brain barrier. These findings suggest that PM causes chronic respiratory diseases, especially asthma, and exacerbate existing ones.…”

Is the epithelial barrier hypothesis the key to understanding the higher incidence and excess mortality during COVID‐19 pandemic? The case of Northern Italy

“…In addition, increased numbers of myeloid dendritic cells that express -cytokines such as IL-1β, IL-6 and IL-23, which stimulate the development of T H 17 cells, were identified in these patients. 42 PM induces direct epithelial barrier disruption via occludin reduction at the plasma membrane and ZO-1 dissociation. 15 Supporting these findings, a significantly weak expression of claudin-1, occludin and ZO-1 in biopsies of patients during a peak inner-city air pollution time in winter compared to summer and PM2.5 in vitro caused an epithelial barrier leakiness.…”