In Situ Studyof Abundant Expression of Proinflammatory Chemokines and Cytokines inPulmonary Granulomas That Develop in Cynomolgus MacaquesExperimentally Infected withMycobacteriumtuberculosis

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Abstract
Tuberculosis remains a major public health problem worldwide. Chemokines and cytokines organize and direct infiltrating cells to sites of infection, and these molecules likely play crucial roles in granuloma formation and maintenance. To address this issue, we used in situ hybridization (ISH) to measure chemokine and cytokine mRNA expression levels and patterns directly in lung tissues from cynomolgus macaques (Macaca fascicularis) experimentally infected with a low dose of virulentMycobacterium tuberculosis. We examined more than 300 granulomas and observed abundant expression of gamma interferon (IFN-γ)-inducible chemokine mRNAs (CXCL9/monokine induced by IFN-γ, CXCL10/IFN-γ-inducible protein, and CXCL11/IFN-γ-inducible T-cell α-chemoattractant) within solid and caseous granulomas, and there was only minimal expression in nongranulomatous regions of tissue. The mRNA expression patterns of IFN-γ and tumor necrosis factor alpha were examined in parallel, and the results revealed that cytokine mRNA+cells were abundant and generally localized to the granulomas. Mycobacterial 16S rRNA expression was also measured by ISH, and the results revealed that there was localization predominantly to the granulomas and that the highest signal intensity was in caseous granulomas. We observed several granulomatous lesions with exceptionally high levels of RNA for mycobacterial 16S rRNA, IFN-γ, and IFN-γ-inducible chemokines, suggesting that the local presence of mycobacteria is partially responsible for the upregulation of IFN-γ-inducible chemokines and recruitment of CXCR3+cells, which were also abundant in granulomatous lesions. These results suggest that expression of CXCR3 ligands and the subsequent recruitment of CXCR3+cells are involved in granuloma formation and maintenance.

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