Angiotensin-II enhances immune defense and bacterial clearance in sepsis

What is it about?

Sepsis, a dysregulated immune response to infection is cause of 1-in-5 deaths worldwide and the leading cause of death in US hospitals. Sepsis often causes life-threateningly low blood pressure that requires treatment with vasopressor medications such as norepinephrine. However, immunosuppression is an increasingly recognized component of immune dysregulation in sepsis, and norepinephrine is immunosuppressive. Therefore, while treatment is required to raise blood pressure – in order to maintain oxygen delivery to tissues – norepinephrine may worsen the underlying immune dysregulation that leads to sepsis in the first place. Angiotensin-II, a peptide hormone of the renin-angiotensin system, is an alternative therapy that was recently approved to treat low blood pressure in sepsis. Decades of work have found that angiotensin-II has complex effects on immunity and inflammation in chronic disease states, but whether angiotensin-II impacts immune function in severe bacterial infections had been unexplored. This study found that angiotensin-II treatment enhanced innate immune bacterial killing functions, increased bacterial clearance, and modulate systemic inflammatory responses without increasing inflammatory injury in a mouse model of sepsis. These benefits were not seen with norepinephrine treatment. The reproducibility of findings was confirmed at an independent laboratory. Experiments using a genetically modified mouse strain that selectively does not express the angiotensin-II receptor on specific immune cell populations further confirmed the bacterial defense effects of angiotensin-II were mediated through the immune system. Importantly, angiotensin-II increased certain immune cells (monocytes) ability to engulf bacteria (phagocytosis) and produce bacterial-killing molecules (reactive oxygen species; ROS) when these cells were co-stimulated with the bacterial molecule lipopolysaccharide (LPS), but angiotensin-II had no effect in the absence of LPS, indicating the effect to increase immune function required the presence of a bacterial stimulus.

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Photo by National Cancer Institute on Unsplash

Photo by National Cancer Institute on Unsplash

Why is it important?

This study both informs our understanding of how the body defends against bacterial infection and suggests a new treatment for immune dysfunction in the severe infections that lead to sepsis. From a biological standpoint, angiotensin-II, a hormone commonly inhibited as a treatment for chronic cardiovascular disease, appears to play a key and previously unknown role in how the body defends against severe bacterial infections. Clinically, there remain no proven treatments targeting immune dysregulation in sepsis. The immune supporting effects seen in this study suggest angiotensin-II may have a role in sepsis treatment not just to increase blood pressure, but also as an immunomodulator directed at reversing septic immune dysfunction. The findings that angiotensin-II required LPS co-stimulation to increase monocyte phagocytosis and ROS production and that angiotensin-II did not worsen systemic inflammation or organ dysfunction are particularly important because they suggest angiotensin-II can support the immune system in defending against severe infection without increasing collateral inflammatory organ injury.