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.
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
Schematic representation of Ang-(1-7) mechanisms in macrophage migration and function favoring resolution of inflammation.