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,
* Curriculum in Genetics and Molecular Biology,
Lineberger Comprehensive Cancer Center,
Department of Microbiology and Immunology,
Curriculum in Oral Biology, and
¶ Department of Medicine, Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC 27599
Bacterial infection elicits a range of beneficial as well as detrimental host inflammatory responses. Key among these responses are macrophage/monocyte necrosis, release of the proinflammatory factor high-mobility group box 1 protein (HMGB1), and induction of the cytokine IL-1. Although the control of IL-1β has been well studied, processes that control macrophage cell death and HMGB1 release in animals are poorly understood. This study uses Klebsiella pneumonia as a model organism because it elicits all three responses in vivo. The regulation of these responses is studied in the context of the inflammasome components NLRP3 and ASC, which are important for caspase-1 activation and IL-1β release. Using a pulmonary infection model that reflects human infection, we show that K. pneumonia-induced mouse macrophage necrosis, HMGB1, and IL-1β release are dependent on NLRP3 and ASC. K. pneumoniae infection of mice lacking Nlrp3 results in decreased lung inflammation and reduced survival relative to control, indicating the overall protective role of this gene. Macrophage/monocyte necrosis and HMGB1 release are controlled independently of caspase-1, suggesting that the former two responses are separable from inflammasome-associated functions. These results provide critical in vivo validation that the physiologic role of NLRP3 and ASC is not limited to inflammasome formation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI63031, AI67798, AI067798, and AI077437. I.C.A. was by Lineberger Comprehensive Cancer Center Basic Science Research Program Fellowship T32CA009156 and Thurston Arthritis Center Fellowship T32AR007416. He is also the recipient of a National Institutes of Health National Research Service Award postdoctoral fellowship. J.A.D. was supported by the University of North Carolina Clinical Translation Science Award/K12 Scholars Program, National Institutes of Health Grant KL2RR025746, and the Burroughs Wellcome Fund Career Award for Medical Scientists. J.B. was supported by National Institute of Allergy and Infectious Diseases Grant R21-AI061059.
2 S.B.W., I.C.A., and D.T.B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Jenny Pan-Yun Ting, Campus Box No. 7295, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 27599-7295. E-mail address: panyun{at}med.unc.edu
4 Abbreviations used in this paper: HMGB1, high-mobility group box protein 1; 7-AAD, 7-aminoactinomycin D; BALF, bronchoalveolar lavage fluid; BMDM, bone marrow-derived macrophage; CTRL, control; LDH, lactate dehydrogenase; MOI, multiplicity of infection; PARP, poly(ADP-ribose) polymerase; sh, short hairpin; WT, wild type.
5 The online version of this article contains supplemental material.
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