While tuberculosis susceptibility has historically been ascribed to failed inflammation, it is now known that an excess of leukotriene A4 hydrolase (LTA4H), which catalyzes the final step in leukotriene B4 (LTB4) synthesis, produces a hyperinflammatory state and tuberculosis susceptibility. Here we show that the LTB4-inactivating enzyme leukotriene B4 dehydrogenase/prostaglandin reductase 1 (LTB4DH/PTGR1) restricts inflammation and independently confers resistance to tuberculous infection. LTB4DH overexpression counters the susceptibility resulting from LTA4H excess while ltb4dh-deficient animals can be rescued pharmacologically by LTB4 receptor antagonists. These data place LTB4DH as a key modulator of TB susceptibility and suggest new tuberculosis therapeutic strategies.
References
[1]
Agarwal N, Lamichhane G, Gupta R, Nolan S, Bishai WR (2009) Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase. Nature 460: 98–102.
[2]
Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, et al. (2012) Host Genotype-Specific Therapies Can Optimize the Inflammatory Response to Mycobacterial Infections. Cell 148: 434–446.
[3]
Bafica A, Scanga CA, Serhan C, Machado F, White S, et al. (2005) Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. The Journal of clinical investigation 115: 1601–1606.
[4]
Haeggstrom JZ, Funk CD (2011) Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chemical reviews 111: 5866–5898.
[5]
Serhan CN (2007) Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annual review of immunology 25: 101–137.
[6]
Roca FJ, Ramakrishnan L (2013) TNF Dually Mediates Resistance And Susceptibility To Mycobacteria Via Mitochondrial Reactive Oxygen Species. Cell In press.
[7]
el-Ahmady O, Mansour M, Zoeir H, Mansour O (1997) Elevated concentrations of interleukins and leukotriene in response to Mycobacterium tuberculosis infection. Annals of clinical biochemistry 34 (Pt 2): 160–164.
[8]
Yokomizo T, Izumi T, Takahashi T, Kasama T, Kobayashi Y, et al. (1993) Enzymatic inactivation of leukotriene B4 by a novel enzyme found in the porcine kidney. Purification and properties of leukotriene B4 12-hydroxydehydrogenase. The Journal of biological chemistry 268: 18128–18135.
[9]
Yokomizo T, Ogawa Y, Uozumi N, Kume K, Izumi T, et al. (1996) cDNA cloning, expression, and mutagenesis study of leukotriene B4 12-hydroxydehydrogenase. The Journal of biological chemistry 271: 2844–2850.
[10]
Shak S, Goldstein IM (1984) Omega-oxidation is the major pathway for the catabolism of leukotriene B4 in human polymorphonuclear leukocytes. The Journal of biological chemistry 259: 10181–10187.
[11]
Soberman RJ, Harper TW, Murphy RC, Austen KF (1985) Identification and functional characterization of leukotriene B4 20-hydroxylase of human polymorphonuclear leukocytes. Proceedings of the National Academy of Sciences of the United States of America 82: 2292–2295.
[12]
Maddox JF, Serhan CN (1996) Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. The Journal of experimental medicine 183: 137–146.
[13]
Hori T, Yokomizo T, Ago H, Sugahara M, Ueno G, et al. (2004) Structural basis of leukotriene B4 12-hydroxydehydrogenase/15-Oxo-prostagla？ndin13-reductase catalytic mechanism and a possible Src homology 3 domain binding loop. The Journal of biological chemistry 279: 22615–22623.
[14]
Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, et al. (2007) Population genomics of human gene expression. Nature genetics 39: 1217–1224.
[15]
Serezani CH, Perrela JH, Russo M, Peters-Golden M, Jancar S (2006) Leukotrienes are essential for the control of Leishmania amazonensis infection and contribute to strain variation in susceptibility. Journal of immunology 177: 3201–3208.
[16]
Nicolete R, Secatto A, Pereira PA, Soares EG, Faccioli LH (2009) Leukotriene B4-loaded microspheres as a new approach to enhance antimicrobial responses in Histoplasma capsulatum-infected mice. International journal of antimicrobial agents 34: 365–369.
[17]
Mancuso P, Lewis C, Serezani CH, Goel D, Peters-Golden M (2010) Intrapulmonary administration of leukotriene B4 enhances pulmonary host defense against pneumococcal pneumonia. Infection and immunity 78: 2264–2271.
[18]
Hallstrand TS, Henderson WR Jr (2010) An update on the role of leukotrienes in asthma. Current opinion in allergy and clinical immunology 10: 60–66.
[19]
Back M, Hansson GK (2006) Leukotriene receptors in atherosclerosis. Annals of medicine 38: 493–502.
[20]
Rae SA, Davidson EM, Smith MJ (1982) Leukotriene B4, an inflammatory mediator in gout. Lancet 2: 1122–1124.
[21]
Mathis S, Jala VR, Haribabu B (2007) Role of leukotriene B4 receptors in rheumatoid arthritis. Autoimmunity reviews 7: 12–17.
[22]
Spite M, Hellmann J, Tang Y, Mathis SP, Kosuri M, et al. (2011) Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. Journal of immunology 187: 1942–1949.
[23]
Chen X, Li N, Wang S, Wu N, Hong J, et al. (2003) Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin. Journal of the National Cancer Institute 95: 1053–1061.
[24]
Yokomizo T, Kato K, Terawaki K, Izumi T, Shimizu T (2000) A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. The Journal of experimental medicine 192: 421–432.
[25]
Zhao Y, Weng CC, Tong M, Wei J, Tai HH (2010) Restoration of leukotriene B(4)-12-hydroxydehydrogenase/15- oxo-prostaglandin 13-reductase (LTBDH/PGR) expression inhibits lung cancer growth in vitro and in vivo. Lung cancer 68: 161–169.
[26]
Wei L, Liu J, Le XC, Han Y, Tong Y, et al. (2011) Pharmacological induction of leukotriene B4–12-hydroxydehydrogenase suppresses the oncogenic transformation of human hepatoma HepG2 cells. International journal of oncology 39: 735–745.
[27]
Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, et al. (2011) Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145: 39–53.
[28]
Cosma CL, Klein K, Kim R, Beery D, Ramakrishnan L (2006) Mycobacterium marinum Erp is a virulence determinant required for cell wall integrity and intracellular survival. Infection and immunity 74: 3125–3133.
[29]
Cosma CL, Swaim LE, Volkman H, Ramakrishnan L, Davis JM (2006) Zebrafish and frog models of Mycobacterium marinum infection. Current protocols in microbiology Chapter 10: Unit 10B 12.
[30]
Davis JM, Clay H, Lewis JL, Ghori N, Herbomel P, et al. (2002) Real-time visualization of mycobacterium-macrophage interactions leading to initiation of granuloma formation in zebrafish embryos. Immunity 17: 693–702.
[31]
Roca FJ, Mulero I, Lopez-Munoz A, Sepulcre MP, Renshaw SA, et al. (2008) Evolution of the inflammatory response in vertebrates: fish TNF-alpha is a powerful activator of endothelial cells but hardly activates phagocytes. Journal of immunology 181: 5071–5081.
[32]
Tobin DM, Vary JC Jr, Ray JP, Walsh GS, Dunstan SJ, et al. (2010) The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140: 717–730.
