Dietary cadmium levels potentiate H1N1-mediated lung inflammation and kynurenine metabolism in mice
Joshua D. Chandler1, Xin Hu1, Eunju Ko2, Soojin Park2, Jolyn Fernandes1, Michael L. Orr1, Young-Tae Lee2, Dean P. Jones1, Sang-Moo Kang2 and Young-Mi Go1.
Influenza A virus subtype H1N1 is seasonally active in the United States, affecting millions of people each year and claiming tens of thousands of lives since the 2009 pandemic. Public health efforts have focused on vaccination to prevent serious infections, but exposed individuals whobecome sick face severe inflammation which may result in death. The ubiquitous heavy metal cadmium (Cd) is a pro-inflammatory agent, and while occupational and smoking exposures have decreased, dietary exposure remained constant during the 1999-2008 U.S. NHANES survey, potentially contributing to multiple organ diseases. Emerging evidence suggests that dietary Cd is detrimental to lung function at levels achievable in the diet. To assess the role of dietary Cd in lung inflammation, we exposed 8-week old male C57BL6/J mice to 1 mg/L (5.5 µM) CdCl2in drinking water for 16 weeks. 10 days prior to completion of 16 weeks, mice were intranasally exposed to a sub-lethal dose of H1N1 or sterile saline vehicle. H1N1 caused a 20% body weight loss and a 7-fold increase in airway hyperresponsiveness by the 10th day of infection, while Cdexposure caused a 4.8-fold increase in lung tissue Cd without detectable changes in urine or plasma. Furthermore, Cd-exposed mice had significantly higher H1N1-mediated inflammation in airways, lung blood vessels and lung interstitial spaces. Inflammation was comprised of neutrophils, monocytes, T cells and dendritic cells. Cd also increased alveolar macrophages in infected and uninfected mice, while H1N1 decreased their numbers. Pro-inflammatory cytokines, chiefly those involved in IFN-γ, TNF-α and chemotactic pathways, were increased Cd-exposed infected mice compared to vehicle-treated infected mice. Lung inflammation was associated with altered tryptophan metabolism via the kynurenine pathway, which was further disrupted by Cd through the induction of kynureninase mRNA (Kynu). Gene set enrichment showed Kynu induction by Cd and tryptophan metabolism contributed to enhanced TNF-α signaling via NF-κB in infected mice exposed to Cd. Ultimately, low dose Cd exposure elevated lung tissue Cd burden and exacerbated pro-inflammatory responses to sub-lethal H1N1 by promoting kynurenine metabolism. Therefore, dietary Cd may contribute to more severe lung inflammation during influenza infections, worsening clinical outcomes and increasing public health risk.
1. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia
2. Microbiology and Immunology, Emory University, Atlanta, Georgia