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Title: Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model.
Austin Authors: Leisman, Daniel E;Privratsky, Jamie R;Lehman, Jake R;Abraham, Mabel N;Yaipan, Omar Y;Brewer, Mariana R;Nedeljkovic-Kurepa, Ana;Capone, Christine C;Fernandes, Tiago D;Griffiths, Robert;Stein, William J;Goldberg, Marcia B;Crowley, Steven D;Bellomo, Rinaldo ;Deutschman, Clifford S;Taylor, Matthew D
Affiliation: Department of Intensive Care, Royal Melbourne Hospital, Parkville, VIC 3050, Australia..
Broad Institute of MIT and Harvard, Cambridge, MA 02142..
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114..
Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia..
Intensive Care
Department of Medicine, Massachusetts General Hospital, Boston, MA 02114..
Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Hofstra-Northwell School of Medicine, Manhasset, NY 11030..
Division of Critical Care Medicine, Department of Anesthesiology, Duke University, Durham, NC 27708..
Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, NY 11040..
Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27705..
Center for Bacterial Pathogenesis, Division of Infectious Disease, Massachusetts General Hospital, Boston, MA 02114..
Department of Medicine, Harvard Medical School, Boston, MA 02115..
Department of Microbiology, Harvard Medical School, Boston, MA 02115..
Department of Critical Care, University of Melbourne, Melbourne, VIC 3010, Australia..
Issue Date: 23-Aug-2022
Date: 2022
Publication information: Proceedings of the National Academy of Sciences of the United States of America 2022; 119(34): e2211370119
Abstract: 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.
DOI: 10.1073/pnas.2211370119
ORCID: 0000-0001-9670-9425
Journal: Proceedings of the National Academy of Sciences of the United States of America
PubMed URL: 35969740
PubMed URL:
Type: Journal Article
Subjects: angiotensin II
renin-angiotensin system
vasoconstrictor agents
Appears in Collections:Journal articles

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