Regulatory T cells and IL10 suppress pulmonary host defense during early-life exposure to radical containing combustion derived ultrafine particulate matter

Abstract

BackgroundExposure to elevated levels of particulate matter (PM) is associated with increased risk of morbidity and mortality due to respiratory tract viral infections in infants. Recent identification of environmentally persistent free radicals (EPFRs) in the PM from a variety of combustion sources suggests its role in the enhancement of disease severity of lower respiratory tract infections (LRTI). Our previous studies demonstrated that acute exposure to EPFRs induces pulmonary immunosuppression allowing for enhanced influenza disease severity. Here, we determine the mechanism of EPFR-induced immunosuppression and its impact on the immune response towards influenza infection.MethodsNeonatal mice (3 days old) were acutely exposed to DCB (combustion derived PM with chemisorbed EPFR) for seven consecutive days. Four days post-exposure (dpe), mice were infected with influenza virus. Pulmonary T cell phenotypes including regulatory T cells (Tregs) were analyzed by flow cytometry. The role of IL10 in EPFR-induced exacerbation of influenza disease severity was determined by administering recombinant IL10 (rIL10) to wild type mice or by using IL10 deficient (IL10−/−) neonatal mice. Mice were assessed for morbidity by measuring percent weight change and pulmonary viral load.ResultsNeonatal mice exposed to EPFRs had a significant increase in pulmonary Tregs and the immunosuppressive cytokine IL10 following influenza infection, which coincided with decreased protective T cell responses to influenza infection at 6 dpi. Depletion of Tregs in EPFR-exposed neonatal mice resulted in increased protective, adaptive T cell responses, whereas adoptive transfer of Tregs from EPFR-exposed neonates to air-exposed neonatal mice suppressed adaptive T cell responses towards influenza infection. Further, treatment with rIL10 could recapitulate EPFR-induced exacerbation of morbidity and pulmonary viral load compared to air exposed and influenza infected mice, whereas, EPFR-exposed IL10−/− neonates exhibited significant reductions in morbidity, pulmonary viral load and adaptive T cell responses following influenza infection.ConclusionsNeonatal exposure to EPFRs induced Tregs and IL10 resulting in suppressed adaptive T cell responses and enhanced influenza disease severity in neonatal mice. Depletion of Tregs increased adaptive T cell responses and deficiency of IL10 reduced morbidity and conferred enhanced protection against influenza virus.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0487-4) contains supplementary material, which is available to authorized users.

In utero ultrafine particulate matter exposure causes offspring pulmonary immunosuppression

“…A transient increase in Treg cells likely underlies a decreased inflammatory response. In other models, an increase in pulmonary Treg cells after neonatal CDPM exposure, driven by IL-10 signaling, correlated with increased susceptibility to viral infection (45, 46). We were unable to distinguish Treg cells (i.e., Foxp3+ cells) between FA- and PM-exposed groups using immunohistochemistry in our model; future investigation using flow cytometry may shed light on the role of specific immune subpopulations in the observed response.…”

SARS‐CoV‐2 infection, COVID‐19 pathogenesis, and exposure to air pollution: What is the connection?

“…225 Infection with influenza A virus after exposure of neonatal mice to combustion-derived PM increased pulmonary T reg cells, and IL-10 levels, suppressing protective T cell responses. 226 Severe SARS-CoV infection is characterized by delayed development of adaptive immune responses and prolonged viral clearance caused by the dramatic loss of CD4 + and CD8 + T cells early in infection, 227 and overactivation of remaining T H 17 and cytotoxic CD8 + T cells (perforin-and granulysin-positive cells) has been linked to severe immune injuries in COVID-19. 228 Thus, PM exposure may suppress antiviral adaptive responses, promoting SARS-CoV-2 replication and dissemination (Fig.…”

The role of air pollution (PM and NO2) in COVID-19 spread and lethality: A systematic review

“…Ambient particulate matter (PM) induces its pro-inflammatory and thrombogenic effects through the generation of oxidative stress by its chemical compounds and metals ( Li et al, 2008 ; Signorelli et al, 2019 ). The recent identification of environmentally persistent free radicals (EPFRs) in the PM, resulting from a mixture of combustion sources, theorize its role in the increase of disease severity of lower respiratory tract infections (LRTI) ( Jaligama et al, 2017 ). Scientific evidences support that short- and long-term exposures to ambient air pollutants are associated with a broad of adverse health outcomes ( Ferrante and Conti, 2017 ; Fiore et al, 2019 ), such as higher mortality rates, greater hospital admissions and increased outpatient visits ( Bremner et al, 1999 ; Cohen et al, 2017 ; Dehghani et al, 2017 ; Dockery et al, 1993 ).…”