Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis
Isabella Zaidan, … , Izabela Galvão, Lirlândia P. Sousa
Isabella Zaidan, … , Izabela Galvão, Lirlândia P. Sousa
Published December 7, 2021
Citation Information: JCI Insight. 2022;7(1):e147819. https://doi.org/10.1172/jci.insight.147819.
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Research Article Infectious disease Inflammation

Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis

Abstract

Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2–dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.

Authors

Isabella Zaidan, Luciana P. Tavares, Michelle A. Sugimoto, Kátia M. Lima, Graziele L. Negreiros-Lima, Lívia C.R. Teixeira, Thais C. Miranda, Bruno V.S. Valiate, Allysson Cramer, Juliana Priscila Vago, Gabriel H. Campolina-Silva, Jéssica A.M. Souza, Laís C. Grossi, Vanessa Pinho, Maria Jose Campagnole-Santos, Robson A.S. Santos, Mauro M. Teixeira, Izabela Galvão, Lirlândia P. Sousa

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Figure 3

Ang-(1-7) induces time-dependent recruitment of monocytes/macrophages to the pleura of mice and increases IL-10 production.

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Ang-(1-7) induces time-dependent recruitment of monocytes/macrophages to...
BALB/c mice received an intrapleural (i.pl.) injection of Ang-(1-7) (100 ng/cavity) or PBS (controls), and the cells recruited to the cavity were harvested at 6, 24, and 48 hours for total and differential leukocyte counts by light microscopy (A). Levels of CCL2 and IL-10 were measured by ELISA in the pleural lavage supernatants after PBS or Ang-(1-7) injections (B). Flow cytometry analysis of recruited leukocytes harvested 48 hours after Ang-(1-7) or PBS injection was also performed. Representative dot plots (C), leukocyte frequencies (expressed as the percentage of single cells), and leukocyte numbers are presented (D and E). Results are presented as mean ± SEM (graphs A n = 5, B n = 6, D and E n = 8), * for P < 0.05 and ** for P < 0.01 when compared with control (PBS), by 1-way ANOVA.