Early Life Ozone Exposure Results in Dysregulated Innate Immune Function and Altered microRNA Expression in Airway Epithelium

Abstract

Exposure to ozone has been associated with increased incidence of respiratory morbidity in humans; however the mechanism(s) behind the enhancement of susceptibility are unclear. We have previously reported that exposure to episodic ozone during postnatal development results in an attenuated peripheral blood cytokine response to lipopolysaccharide (LPS) that persists with maturity. As the lung is closely interfaced with the external environment, we hypothesized that the conducting airway epithelium of neonates may also be a target of immunomodulation by ozone. To test this hypothesis, we evaluated primary airway epithelial cell cultures derived from juvenile rhesus macaque monkeys with a prior history of episodic postnatal ozone exposure. Innate immune function was measured by expression of the proinflammatory cytokines IL-6 and IL-8 in primary cultures established following in vivo LPS challenge or, in response to in vitro LPS treatment. Postnatal ozone exposure resulted in significantly attenuated IL-6 mRNA and protein expression in primary cultures from juvenile animals; IL-8 mRNA was also significantly reduced. The effect of antecedent ozone exposure was modulated by in vivo LPS challenge, as primary cultures exhibited enhanced cytokine expression upon secondary in vitro LPS treatment. Assessment of potential IL-6-targeting microRNAs miR-149, miR-202, and miR-410 showed differential expression in primary cultures based upon animal exposure history. Functional assays revealed that miR-149 is capable of binding to the IL-6 3′ UTR and decreasing IL-6 protein synthesis in airway epithelial cell lines. Cumulatively, our findings suggest that episodic ozone during early life contributes to the molecular programming of airway epithelium, such that memory from prior exposures is retained in the form of a dysregulated IL-6 and IL-8 response to LPS; differentially expressed microRNAs such as miR-149 may play a role in the persistent modulation of the epithelial innate immune response towards microbes in the mature lung.

miR‐410 suppresses the expression of interleukin‐6 as well as renal fibrosis in the pathogenesis of lupus nephritis

“…To date, numerous studies have provided evidence that miRNAs play a critical role in the development of LN . It has been confirmed that miR‐410 is capable of binding to the IL‐6 3′UTR and decreasing IL‐6 protein synthesis in airway epithelial cell lines . Since we have found that IL‐6 was overexpressed while miR‐410 was decreased in MRL/lpr mice (Fig.…”

“…While some studies have classically focused on the dysregulation of adaptive immunity in LN, miRNAs have been identified as major regulators of disease pathogenesis. Furthermore, recent studies highlight the significance of miRNAs (miR‐149, miR‐202, and miR‐410) in the aberrant expression or function of immune factors . However, despite these significant advances, the scarcity of novel therapies continues.…”

“…18 It has been confirmed that miR-410 is capable of binding to the IL-6 3 0 UTR and decreasing IL-6 protein synthesis in airway epithelial cell lines. 19 Since we have found that IL-6 was overexpressed while miR-410 was decreased in MRL/lpr mice ( Fig. 1e,h), to investigate the underlying mechanism of how IL-6 was induced in the kidney of MRL/lpr mice, the intact 3 0 UTR of IL-6 was cloned into luciferase reporter plasmids.…”

RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

“…The upregulation of miR‐494 might be beneficial as it prevents ischemia‐reperfusion injury 37. The downregulation of miR‐149‐5p may contribute to the induction of genes downstream of the proinflammatory cytokine IL‐6 38, which we also observed in our mRNA arrays.…”

An epigenome-wide association study of total serum IgE in Hispanic children

“…There are some novel findings on top of the results (Table E3), including methylation in the genes for microRNA 202 ( MIR202 ), lipin 1 ( LPIN1 ), and prostaglandin D2 receptor 2 ( PTGDR2 ). MIR202 is differentially expressed in cultured airway epithelial cells of monkeys in response to ozone exposure and lipopolysaccharide (LPS) treatment 26 , and is decreased in bronchoalveolar lavage (BAL) of patients with sarcoidosis 27 . LPIN1 , which has been implicated in lipid metabolism and rhabdomyolisis, encodes a magnesium-ion-dependent phosphatidic acid phosphohydrolase enzyme.…”