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.
Highlights
The renin-angiotensin system (RAS) is traditionally viewed as an enzymatic cascade of reactions that culminate with the production of angiotensin II (Ang II), a hormone peptide that causes vasoconstriction and is endowed with potent proinflammatory actions (1)
Since Ang-(1-7) bioactions are mainly translated by Mas receptor (MasR) binding (6), we evaluated the involvement of MasR in the Ang-(1-7)–induced macrophage migration
Resolution of inflammation is a time-regulated process that results in the termination of the inflammatory response to restore tissue homeostasis (33)
Summary
The renin-angiotensin system (RAS) is traditionally viewed as an enzymatic cascade of reactions that culminate with the production of angiotensin II (Ang II), a hormone peptide that causes vasoconstriction and is endowed with potent proinflammatory actions (1). RAS activation is often associated with the pathological induction of inflammatory and profibrotic responses in different diseases (2, 3). An alternative counterregulatory branch of the RAS was later described: the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis. Angiotensin-(1-7) [Ang-(1-7)] is a bioactive heptapeptide produced through the enzymatic inactivation of Ang II by the angiotensin-converting enzyme 2 (ACE-2) (4, 5). In addition to directly inhibiting Ang II, the production and bioactions of Ang-(1-7) include potent receptor-mediated antiinflammatory responses triggered by the activation of the G protein–coupled receptor Mas (MasR) (6). MasR absence is associated with the aggravation of cardiovascular and inflammatory diseases (7–10)
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