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Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):E2997-3006. doi: 10.1073/pnas.1301128110. Epub 2013 Jul 23.

Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis.

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  • 1Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA. dasrit@mail.med.upenn.edu

Abstract

Macrophage migration inhibitory factor (MIF), an innate cytokine encoded in a functionally polymorphic genetic locus, contributes to detrimental inflammation but may be crucial for controlling infection. We explored the role of variant MIF alleles in tuberculosis. In a Ugandan cohort, genetic low expressers of MIF were 2.4-times more frequently identified among patients with Mycobacterium tuberculosis (TB) bacteremia than those without. We also found mycobacteria-stimulated transcription of MIF and serum MIF levels to be correlated with MIF genotype in human macrophages and in a separate cohort of US TB patients, respectively. To determine mechanisms for MIF's protective role, we studied both aerosolized and i.v. models of mycobacterial infection and observed MIF-deficient mice to succumb more quickly with higher organism burden, increased lung pathology, and decreased innate cytokine production (TNF-α, IL-12, IL-10). MIF-deficient animals showed increased pulmonary neutrophil accumulation but preserved adaptive immune response. MIF-deficient macrophages demonstrated decreased cytokine and reactive oxygen production and impaired mycobacterial killing. Transcriptional investigation of MIF-deficient macrophages revealed reduced expression of the pattern recognition receptor dectin-1; restoration of dectin-1 expression recovered innate cytokine production and mycobacterial killing. Our data place MIF in a crucial upstream position in the innate immune response to mycobacteria and suggest that commonly occurring low expression MIF alleles confer an increased risk of TB disease in some populations.

PMID:
23882081
[PubMed - indexed for MEDLINE]
PMCID:
PMC3740876
Free PMC Article
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