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Low-dose mercury heightens early innate response to coxsackievirus infection in female mice

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Abstract

Objective

Mercury is a ubiquitous environmental contaminant with toxic outcomes over a range of exposures. In this study, we investigated the effects of mercury exposure on early immune responses to coxsackievirus B3 (CVB3) infection in a murine model of autoimmune heart disease.

Materials and methods

Female BALB/c mice, susceptible to CVB3-induced autoimmune myocarditis, were treated with mercuric chloride (200 μg/kg body weight every other day for 2 weeks) prior to infection with CVB3. Six hours post-infection, immune cells were isolated from the spleen and peritoneum for flow cytometry, gene expression, and cytokine profiling. Thirty-five days post-infection, hearts were collected for histological examination of immune cell infiltration.

Results

As for male mice, mercury exposure significantly increased autoimmune myocarditis and immune infiltration into the heart. During the innate response 6 h post-infection, mercury increased expression of co-stimulatory molecules and innate immune receptors on peritoneal macrophages. At the same time point, the alternatively activated macrophage gene, arginase, was increased while the classically activated macrophage gene, inducible nitric oxide synthase, was unaffected. Expression of activation markers were decreased on peritoneal B cells with mercury exposure while T cells were unaffected. Mercury increased production of pro-inflammatory mediators in the spleen. Macrophage-recruiting chemokines and activating cytokines, such as CCL2, CCL4, and IL-6, were increased with mercury following CVB3 infection.

Conclusions

Thus, mercury treatment exacerbates autoimmune myocarditis in female mice and alters early innate signaling on peritoneal macrophages. Mercury also modulates the cytokine profile in the spleen toward a macrophage-activating milieu, and upregulates alternatively activated macrophage genes, providing evidence that mercury exposure promotes inflammation in the context of infection.

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Acknowledgments

This work was supported by National Institutes of Health [T32 ES07141 and K99/R00 ES015426 to J.F.N.; R01 HL087033 and R01 HL111938 to D.F.] and the Heinz Family Foundation. The authors would like to thank Dr. Sylvia Frisancho-Kiss for her advice on innate flow cytometry.

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Authors and Affiliations

  1. Department of Pathology, Microbiology and Immunology, University of South Carolina, School of Medicine, 6439 Garner’s Ferry Rd, VA#1 B10, Columbia, SC, 29208, USA

    Kayla L. Penta, Devon L. Shirley & Jennifer F. Nyland

  2. Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, USA

    DeLisa Fairweather, Ellen K. Silbergeld & Jennifer F. Nyland

  3. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, USA

    Noel R. Rose

  4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA

    Noel R. Rose

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  1. Kayla L. Penta
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  2. DeLisa Fairweather
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  3. Devon L. Shirley
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  4. Noel R. Rose
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  5. Ellen K. Silbergeld
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  6. Jennifer F. Nyland
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Correspondence to Jennifer F. Nyland.

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Responsible Editor: Graham R. Wallace.

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Penta, K.L., Fairweather, D., Shirley, D.L. et al. Low-dose mercury heightens early innate response to coxsackievirus infection in female mice . Inflamm. Res. 64, 31–40 (2015). https://doi.org/10.1007/s00011-014-0781-x

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  • DOI: https://doi.org/10.1007/s00011-014-0781-x

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