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Macrophages sense and kill bacteria through carbon monoxide–dependent inflammasome activation
Barbara Wegiel, … , Miguel P. Soares, Leo E. Otterbein
Barbara Wegiel, … , Miguel P. Soares, Leo E. Otterbein
Published October 8, 2014
Citation Information: J Clin Invest. 2014;124(11):4926-4940. https://doi.org/10.1172/JCI72853.
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Research Article Immunology

Macrophages sense and kill bacteria through carbon monoxide–dependent inflammasome activation

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Abstract

Microbial clearance by eukaryotes relies on complex and coordinated processes that remain poorly understood. The gasotransmitter carbon monoxide (CO) is generated by the stress-responsive enzyme heme oxygenase-1 (HO-1, encoded by Hmox1), which is highly induced in macrophages in response to bacterial infection. HO-1 deficiency results in inadequate pathogen clearance, exaggerated tissue damage, and increased mortality. Here, we determined that macrophage-generated CO promotes ATP production and release by bacteria, which then activates the Nacht, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome, intensifying bacterial killing. Bacterial killing defects in HO-1–deficient murine macrophages were restored by administration of CO. Moreover, increased CO levels enhanced the bacterial clearance capacity of human macrophages and WT murine macrophages. CO-dependent bacterial clearance required the NALP3 inflammasome, as CO did not increase bacterial killing in macrophages isolated from NALP3-deficient or caspase-1–deficient mice. IL-1β cleavage and secretion were impaired in HO-1–deficient macrophages, and CO-dependent processing of IL-1β required the presence of bacteria-derived ATP. We found that bacteria remained viable to generate and release ATP in response to CO. The ATP then bound to macrophage nucleotide P2 receptors, resulting in activation of the NALP3/IL-1β inflammasome to amplify bacterial phagocytosis by macrophages. Taken together, our results indicate that macrophage-derived CO permits efficient and coordinated regulation of the host innate response to invading microbes.

Authors

Barbara Wegiel, Rasmus Larsen, David Gallo, Beek Yoke Chin, Clair Harris, Praveen Mannam, Elzbieta Kaczmarek, Patty J. Lee, Brian S. Zuckerbraun, Richard Flavell, Miguel P. Soares, Leo E. Otterbein

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Figure 8

CO acts therapeutically to inhibit lethal sepsis via the inflammasome.

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CO acts therapeutically to inhibit lethal sepsis via the inflammasome.
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(A) IL-1β in peritoneum from mice infected with E. faecalis (109 CFU) for 1 hour ± CO. Data represent mean ± SD of n = 6/group in triplicate. *P < 0.01; #P < 0.05, CO versus air. (B) Immunoblot of cleaved caspase-1 and IL-1β in PM lysates from mice infected with E. faecalis for 1 hour prior to 1 hour treatment with air or CO. Representative blot from 3 independent experiments. (C) Immunoblots of macrophages lysates from mice treated as in B. (D) ALT in infected mice treated as above. Results represent mean ± SD (n = 4–6/group) from 3 experiments. *P < 0.001, CO versus air. (E) H&E staining 8 hours after E. faecalis ± CO; 6 to 10 images per animal. Arrows indicate lesions. Original magnification, ×20. (F) Bacterial counts in peritoneal lavagates. Inset: IVIS images. Results represent mean ± SD of 6 to 8/group. *P < 0.05; **P < 0.01. (G) Survival in mice injected with lethal E. coli (1010 CFU, i.p.) or CLP ± 4 hours CO initiated 6 hours later. P < 0.02, air + CLP versus CO + CLP; P < 0.02, air + E. coli versus CO + E. coli. (H) Survival of WT and Nalp3–/– mice treated as in G with or without CO (started 1 or 6 hours after bacteria). CO was unable to protect Nalp3–/– mice (P < 0.01). (I) Bacteria counts in peritoneum of E. coli–infected mice. Results represent mean ± SD of 4 to 6/group repeated twice. *P < 0.03, CO versus air; #P < 0.05, Casp1–/– versus Casp1+/+ in both air and CO-treated mice. (J) Survival ± Sn-PP-IX to block HO-1 then ± 4 hours CO beginning 1 hour after bacteria. P < 0.05, 10/group. (K) Survival of indicated mice ± CO as in G. P < 0.03. n = 10–30/group.
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