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

2022-08-23

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

angiotensin II

immunity

innate

renin-angiotensin system

sepsis

vasoconstrictor agents

Journal Article

0000-0001-9670-9425

0000-0001-7965-5402

0000-0003-4266-9733

0000-0002-1650-8939

10.1073/pnas.2211370119

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.

link

Proceedings of the National Academy of Sciences of the United States of America 2022; 119(34): e2211370119

Proceedings of the National Academy of Sciences of the United States of America