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

Research output: Contribution to journalArticlepeer-review

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
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number34
DOIs
StatePublished - 23 Aug 2022
Externally publishedYes

Keywords

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

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