Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death A RT I C L E e n i c i d e M l a t n e m i r e p x E f o l a n r u o J e h T CORRESPONDENCE Heinz G. Remold: hremold@rics.bwh.harvard.edu Abbreviations used: 5-LO, 5-lipoxygenase; AA, arachidonic acid; COX, cyclooxygenase; cPLA2, cytosolic PLA2; EP, E prostanoid; LC-MS-MS, liquid chromatography tandem mass spectrometry; MOI, multi- plicity of infection; mPGES, microsomal prostaglandin E synthase; MPT, mitochondrial permeability transition; PI, propidium iodide; PI3K, phos- phatidylinositol-3 kinase; PKA, protein kinase A; siRNA, small interfering RNA. The Rockefeller University Press $30.00 J. Exp. Med. Vol. 205 No. 12 2791-2801 www.jem.org/cgi/doi/10.1084/jem.20080767 Minjian Chen,1 Maziar Divangahi,1 Huixian Gan,1 Daniel S.J. Shin,1 Song Hong,2 David M. Lee,1 Charles N. Serhan,2 Samuel M. Behar,1 and Heinz G. Remold1 1Department of Medicine and Division of Rheumatology, Immunology, and Allergy and 2Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 Virulent Mycobacterium tuberculosis (Mtb) induces a maladaptive cytolytic death modality, necrosis, which is advantageous for the pathogen. We report that necrosis of macrophages infected with the virulent Mtb strains H37Rv and Erdmann depends on predominant LXA4 production that is part of the antiinflammatory and inflammation-resolving action induced by Mtb. Infection of macrophages with the avirulent H37Ra triggers production of high levels of the prostanoid PGE2, which promotes protection against mitochondrial inner membrane perturbation and necrosis. In contrast to H37Ra infection, PGE2 production is significantly reduced in H37Rv-infected macrophages. PGE2 acts by engaging the PGE2 receptor EP2, which induces cyclic AMP production and protein kinase A activation. To verify a role for PGE2 in control of bacterial growth, we show that infection of prostaglan- din E synthase (PGES) / macrophages in vitro with H37Rv resulted in significantly higher bacterial burden compared with wild-type macrophages. More importantly, PGES / mice harbor significantly higher Mtb lung burden 5 wk after low-dose aerosol infection with virulent Mtb. These in vitro and in vivo data indicate that PGE2 plays a critical role in inhibition of Mtb replication. Tuberculosis is the predominant cause for mortal- ity from chronic pulmonary bacterial infections worldwide causing nearly two million deaths yearly. Tuberculosis has become more serious as a consequence of the global AIDS epidemic and the emergence of multidrug-resistant Mycobacte- rium tuberculosis (Mtb), the causative agent of tu- berculosis (1). Natural transmission of Mtb occurs predominantly via inhalation of aerosols contain- ing small numbers of bacteria that are deposited in the distal airways of the lung (2). The pathogens are phagocytosed by pulmonary M , which serve as a sanctuary for Mtb (3). Virulent Mtb, which M. Divangahi and H. Gan contributed equally to this study. M. Chen’s present address is Clinical Research Center, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China. S. Hong’s present address is Louisiana State University Neuro- science Center, New Orleans, LA 70112. The online version of this article contains supplemental material. reside in M , initially evade elimination by the immune system via preventing apoptosis and in- hibiting maturation of the phagosome–lysosome organelle of the host M (4, 5). The net effect is to diminish entry of bacterial proteins into the class II MHC antigen-processing pathway (4) and to create a protected intracellular milieu where ba- cilli remain metabolically active and replication competent (6). For M infected with virulent H37Rv, necrosis characterized by cytolysis is the dominant form of cell death, which affords a pro- tective milieu for Mtb (7, 8). Thus, subversion of cell death toward necrosis is of considerable ad- vantage for the pathogen. © 2008 Chen et al. This article is distributed under the terms of an Attribu- tion–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncom- mercial–Share Alike 3.0 Unported license, as described at http://creativecommons .org/licenses/by-nc-sa/3.0/). 2791