Vitamin D Counteracts an IL-23-dependent IL-17A+IFNγ+ Response Driven by Urban Particulate Matter.
Am J Respir Cell Mol Biol. 2017 May 2. Epub 2017 May 2. PMID: 28463086
Elizabeth H Mann
Urban particulate matter (UPM) air pollution and vitamin D deficiency are detrimentally associated with respiratory health; this is hypothesised to be due in part to regulation of IL-17A, which UPM is reported to promote. Here we use a myeloid (m)DC-memory CD4+ T cell co-culture system to characterize UPM-driven IL-17A+ cells, investigate the mechanism by which UPM-primed DCs promote this phenotype and address evidence for cross-regulation by vitamin D. CD1c+ mDCs were cultured overnight with or without a reference source of UPM and/or active vitamin D (1,25(OH)2D3) before co-culturing with autologous memory CD4+ T cells. Supernatants were harvested for cytokine analysis on day 5 of co-culture and intracellular cytokine staining performed on day 7. UPM-primed DCs increased the proportion of memory CD4+ T cells expressing Th17-associated cytokines IL-17A, IL-17F and IL-22 as well as IFNγ, GM-CSF and granzyme B. Notably, a large proportion of the UPM-driven IL-17A+ cells co-expressed these cytokines, but not IL-10, indicative of a pro-inflammatory Th17 profile. UPM-treated DCs expressed elevated levels of il23 mRNA and increased secretion of IL-23p40. Neutralisation of IL-23 in culture reduced the frequency of IL-17A+IFNγ+ cells without affecting cell proliferation. 1,25(OH)2D3 counteracted the UPM-driven DC maturation and inhibited the frequency of IL-17A+IFNγ+ cells, most prominently when DCs were co-treated with the corticosteroid dexamethasone, whilst maintaining anti-inflammatory IL-10 synthesis. These data indicate that UPM might promote an inflammatory milieu in part by driving an IL-23-driven pro-inflammatory Th17 response. Restoring vitamin D sufficiency may counteract these UPM-driven effects without obliterating important homeostatic immune functions.