JCI Insight (Jan 2022)

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

Journal volume & issue
Vol. 7, no. 1

Abstract

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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.

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