In a new study entitled “Macrophages sense and kill bacteria through carbon monoxide–dependent inflammasome activation” the authors discovered that carbon monoxide (CO) released by macrophages is a key factor in the host defense against pathogens. Their findings open the possibility of new therapeutics for the CO gas in treating lung diseases. The study was published in the November issue of the Journal of Clinical Investigation. These findings relate to other studies involving CO and lung diseases, such as a recent report that identified worsened forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in Scleroderma patients who had capillary density loss. The findings could aid in battling bacterial infections within the lung, particularly for those who are susceptible to chronic infection.
Macrophages, a type of white blood cell, are key cells of the immune system that surveil and attack pathogens by engulfing and digesting it in a process known as phagocytosis. It is known that carbon monoxide (CO) is highly induced in macrophages upon bacterial infections, via increased activity of the stress-activating enzyme heme-oxygenase 1 (HO-1). Accordingly, mice depleted for HO-1 are less efficient in clearing pathogens leading to higher mortality rates.
Now, researchers at the Beth Israel Deaconess Medical Center (BIDMC) discovered that macrophage-generated CO triggers a chain of reactions that culminates in an intensified response by the host to kill bacteria. Using mouse models of sepsis, the authors dissected the CO signaling pathway in the killing of a wide range of bacteria, from Gram-Positive and Gram-Negative bacteria, as well as Mycobacteria tuberculosis.
In the mechanism proposed by the authors, once CO-endogenously generated in macrophages are released, they induce bacteria to produce ATP, therefore marking these metabolically active bacteria to be recognized by macrophages and enhancing killing activity. Moreover, the authors discovered that CO produced in physiological amounts is a key factor for activation of NALP3 inflammasome, a key component of the innate immune system, culminating in bacterial phagocytosis and killing.
Leo E. Otterbein at the Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center (BIDMC) noted, “CO can now be added to the list of cellular mechanisms that macrophages use to defend the host. CO clearly helps the immune cells to produce a faster and more robust response against bacteria. From a clinical perspective, one could envision CO being administered to patients with ongoing infections to help reduce the risk of dangerous complications, such as sepsis, SIRS and, ultimately, multi-organ failure. Our hope is that we will be able to test these applications in clinical trials and provide the body with a new weapon of mass destruction — one the host employs against invading armies of bacteria.”
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