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Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis.

Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis.
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Domingo-Gonzalez R, Das S, Griffiths KL, Ahmed M, Bambouskova M, Gopal R, Gondi S, Muñoz-Torrico M, Salazar-Lezama MA, Cruz-Lagunas A, Jiménez-Álvarez L, Ramirez-Martinez G, Espinosa-Soto R, Sultana T, Lyons-Weiler J, Reinhart TA, Arcos J, de la Luz Garcia-Hernandez M, Mastrangelo MA, Al-Hammadi N, Townsend R, Balada-Llasat JM, Torrelles JB, Kaplan G, Horne W, Kolls JK, Artyomov MN, Rangel-Moreno J, Zúñiga J, Khader SA,


Domingo-Gonzalez R, Das S, Griffiths KL, Ahmed M, Bambouskova M, Gopal R, Gondi S, Muñoz-Torrico M, Salazar-Lezama MA, Cruz-Lagunas A, Jiménez-Álvarez L, Ramirez-Martinez G, Espinosa-Soto R, Sultana T, Lyons-Weiler J, Reinhart TA, Arcos J, de la Luz Garcia-Hernandez M, Mastrangelo MA, Al-Hammadi N, Townsend R, Balada-Llasat JM, Torrelles JB, Kaplan G, Horne W, Kolls JK, Artyomov MN, Rangel-Moreno J, Zúñiga J, Khader SA, (click to view)

Domingo-Gonzalez R, Das S, Griffiths KL, Ahmed M, Bambouskova M, Gopal R, Gondi S, Muñoz-Torrico M, Salazar-Lezama MA, Cruz-Lagunas A, Jiménez-Álvarez L, Ramirez-Martinez G, Espinosa-Soto R, Sultana T, Lyons-Weiler J, Reinhart TA, Arcos J, de la Luz Garcia-Hernandez M, Mastrangelo MA, Al-Hammadi N, Townsend R, Balada-Llasat JM, Torrelles JB, Kaplan G, Horne W, Kolls JK, Artyomov MN, Rangel-Moreno J, Zúñiga J, Khader SA,

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JCI insight 2017 10 052(19) doi 10.1172/jci.insight.92973
Abstract

Mycobacterium tuberculosis (Mtb) is a global health threat, compounded by the emergence of drug-resistant strains. A hallmark of pulmonary tuberculosis (TB) is the formation of hypoxic necrotic granulomas, which upon disintegration, release infectious Mtb. Furthermore, hypoxic necrotic granulomas are associated with increased disease severity and provide a niche for drug-resistant Mtb. However, the host immune responses that promote the development of hypoxic TB granulomas are not well described. Using a necrotic Mtb mouse model, we show that loss of Mtb virulence factors, such as phenolic glycolipids, decreases the production of the proinflammatory cytokine IL-17 (also referred to as IL-17A). IL-17 production negatively regulates the development of hypoxic TB granulomas by limiting the expression of the transcription factor hypoxia-inducible factor 1α (HIF1α). In human TB patients, HIF1α mRNA expression is increased. Through genotyping and association analyses in human samples, we identified a link between the single nucleotide polymorphism rs2275913 in the IL-17 promoter (-197G/G), which is associated with decreased IL-17 production upon stimulation with Mtb cell wall. Together, our data highlight a potentially novel role for IL-17 in limiting the development of hypoxic necrotic granulomas and reducing disease severity in TB.

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