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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 9

Schematic depicting a proposed mechanism of action for HO-1 and CO in bacteria recognition and activation of innate immune defense machinery.

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Schematic depicting a proposed mechanism of action for HO-1 and CO in ba...
As a highly diffusible gas, HO-1 is induced by endotoxin (LPS) from bacteria and generates CO. CO is emitted by the host macrophage and functions to probe and “assess” the environment. If bacteria are present, CO compels the bacteria to generate ATP, which acts as a danger signal for the macrophage. The bacteria-derived ATP binds to a purinergic receptor on the macrophage, leading to changes in intracellular K+ concentrations. This signal in turn activates the inflammasome to drive pathogen clearance.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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