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Papers of the Week

2022 Aug 23

Proc Natl Acad Sci U S A



Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model.


Leisman DE, Privratsky JR, Lehman JR, Abraham MN, Yaipan OY, Brewer MR, Nedeljkovic-Kurepa A, Capone CC, Fernandes TD, Griffiths R, Stein WJ, Goldberg MB, Crowley SD, Bellomo R, Deutschman CS, Taylor MD
Proc Natl Acad Sci U S A. 2022 Aug 23; 119(34):e2211370119.
PMID: 35969740.


Sepsis, defined as organ dysfunction caused by a dysregulated host-response to infection, is characterized by immunosuppression. The vasopressor norepinephrine is widely used to treat low blood pressure in sepsis but exacerbates immunosuppression. An alternative vasopressor is angiotensin-II, a peptide hormone of the renin-angiotensin system (RAS), which displays complex immunomodulatory properties that remain unexplored in severe infection. In a murine cecal ligation and puncture (CLP) model of sepsis, we found alterations in the surface levels of RAS proteins on innate leukocytes in peritoneum and spleen. Angiotensin-II treatment induced biphasic, angiotensin-II type 1 receptor (AT1R)-dependent modulation of the systemic inflammatory response and decreased bacterial counts in both the blood and peritoneal compartments, which did not occur with norepinephrine treatment. The effect of angiotensin-II was preserved when treatment was delivered remote from the primary site of infection. At an independent laboratory, angiotensin-II treatment was compared in LysM-Cre AT1aR (Myeloid-AT1a) mice, which selectively do not express AT1R on myeloid-derived leukocytes, and littermate controls (Myeloid-AT1a). Angiotensin-II treatment significantly reduced post-CLP bacteremia in Myeloid-AT1a mice but not in Myeloid-AT1a mice, indicating that the AT1R-dependent effect of angiotensin-II on bacterial clearance was mediated through myeloid-lineage cells. Ex vivo, angiotensin-II increased post-CLP monocyte phagocytosis and ROS production after lipopolysaccharide stimulation. These data identify a mechanism by which angiotensin-II enhances the myeloid innate immune response during severe systemic infection and highlight a potential role for angiotensin-II to augment immune responses in sepsis.