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 7

The Ang-(1-7)/MasR pathway promotes the recruitment of macrophages, production of CCL2, and phagocytosis of bacteria.

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The Ang-(1-7)/MasR pathway promotes the recruitment of macrophages, prod...
WT mice were infected with E. coli (1 × 106 CFU), and macrophages were harvested at 12 and 48 hours postinfection for MasR expression (A, n = 3). Macrophages from PBS-injected mice were used as controls. Next, infected mice were treated with A779 (200 ng/cavity) or vehicle, and neutrophil numbers at 12 and 48 hours postinfection were evaluated to calculate the resolution intervals (Ri — B). T50, time point when neutrophil numbers reduced to 50% of maximum (n = 7). In addition, WT and MasR–/– mice were infected, and the numbers of neutrophils (C) and macrophages (D) was evaluated at different time points postinfection. CCL2 levels were measured in the cell-free supernatants of the peritoneal lavages at 6 and 48 hours postinfection (E). (F) Graph shows the CFU numbers in the lavage at 6 hours postinfection (n = 5–11). Phagocytosis of bacteria was evaluated in peritoneal macrophages from naive WT and MasR–/– (G) or WT BMDMs pretreated with Ang-(1-7) — 100 nM (H). Results are expressed as CFU of internalized bacteria or percentage of phagocytosis (n = 5–6). In a parallel experiment, macrophages were incubated for another 2 hours after antibiotics to assess the killing of bacteria inside the macrophages by evaluating the number of viable bacteria (CFU counts in LB agar plates — I). Data are presented as the mean ± SEM, * for P < 0.05 and *** for P < 0.001, when compared with the control group (PBS), or # for P < 0.05 when compared with the A779-treated group, by 1-way ANOVA or t test (when comparing 2 groups).