Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis
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
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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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 6

MasR is upregulated during the resolution of inflammation and is important for recruitment of regulatory macrophages.

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MasR is upregulated during the resolution of inflammation and is importa...
BALB/c mice were challenged with LPS (250 ng/cavity, i.pl.) or PBS, and leukocytes from the pleural cavity were harvested after 8, 24, and 48 hours for Western blot analysis of MasR (A) and differential cell counts (B and C). LPS-challenged mice were treated with A779 (200 ng/cavity) or vehicle at 8 and 24 hours post-LPS injection, and leukocytes were harvested at 48 hours for differential cell counts (B and C). Next, WT and MasR–/– mice were also i.pl. challenged with LPS, and neutrophil (D) and mononuclear cell numbers (E) and CCL2 levels (F) were evaluated. Flow cytometry analysis was performed to assess numbers of macrophages (F4/80+CD11b+ — G), monocytes (F4/80–Ly6C+ — H), and neutrophils (F4/80–Ly6G+ — I). Frequencies of CD206+ macrophages are graphed in J and representative gating is shown in K. Results are shown as the mean ± SEM of n = 5–6 mice. * for P < 0.05, ** for P < 0.01, and *** for P < 0.001 when compared with the control group (PBS). ## for P < 0.01 when compared with the 8-hour time point, or as indicated, by 1-way ANOVA (B and C) or 2-way ANOVA (D–K). NSB, nonspecific band.