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

Daniel E. Leisman, Jamie R. Privratsky, Jake R. Lehman, Mabel N. Abraham, Omar Y. Yaipan, Mariana R. Brewer, Ana Nedeljkovic-Kurepa, Christine C. Capone, Tiago D. Fernandes, Robert Griffiths, William J. Stein, Marcia B. Goldberg, Steven D. Crowley, Rinaldo Bellomo, Clifford S. Deutschman, Matthew D. Taylor

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9 Citations (Scopus)

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.

Original languageEnglish
Article numbere2211370119
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number34
DOIs
Publication statusPublished - 15 Aug 2022

Keywords

  • angiotensin II
  • immunity
  • innate
  • renin-angiotensin system
  • sepsis
  • vasoconstrictor agents

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