MEK1/2 Inhibition Promotes Macrophage Reparative Properties

Abstract

Macrophages have important functional roles in regulating the timely promotion and resolution of inflammation. While many of the intracellular signaling pathways involved in the pro-inflammatory responses of macrophages are well characterized, the components that regulate macrophage reparative properties are less well understood. We identified the MEK1/2 pathway as a key regulator of macrophage reparative properties. Pharmacological inhibition of the MEK1/2 pathway (MEKi) significantly increased expression of IL-4/IL-13 (M2) responsive genes in murine bone marrow-derived and alveolar macrophages. Deletion of the MEK1 gene using LysMCre+/+MEK1fl/fl macrophages as an alternate approach yielded similar results. MEKi enhanced STAT6 phosphorylation, and MEKi induced changes in M2 polarization were dependent on STAT6. In addition, MEKi-treatment significantly increased both murine and human macrophage efferocytosis of apoptotic cells (AC) independent of macrophage polarization and STAT6. These phenotypes were associated with increased gene and protein expression of Mertk, Tyro3, and Abca1, three proteins that promote macrophage efferocytosis. We also studied the effects of MEKi on in vivo macrophage efferocytosis and polarization. MEKi treated mice had increased efferocytosis of apoptotic PMNs instilled into the peritoneum. Furthermore, administration of MEKi after LPS-induced lung injury led to improved recovery of weight, fewer neutrophils in the alveolar compartment, and greater macrophage M2 polarization. Collectively, these results show that MEK1/2 inhibition is capable of promoting reparative properties of both murine and human macrophages. These studies suggest that the MEK1/2 pathway may be a therapeutic target to promote the resolution of inflammation via modulation of macrophage functions.

Calreticulin Blockade Attenuates Murine Acute Lung Injury by Inducing Polarization of M2 Subtype Macrophages

“…Therefore, modulation of macrophage activation and polarization is an effective therapeutic approach in the treatment of ARDS/ALI. A body of evidences showed that macrophages can be modulated by many reagents (4)(5)(6)(7). Our previous research revealed that antioxidant resveratrol can attenuate ALI through polarization of alternatively activated macrophage or M2 cells (8).…”

“…On the other hand, CALR suppresses inflammatory responses by increasing macrophage phagocytosis and clearance of dead cells. The beneficial effects of CALR are associated with increased inflammation resolution and damaged tissue repair (7,37). However, it remains unknown whether CALR plays an important role in the progression of ARDS/ALI.…”

MEK1 regulates pulmonary macrophage inflammatory responses and resolution of acute lung injury

“…In an effort to understand signaling pathways regulating macrophage activation, we identified the mitogen-activated protein kinases MEK1 (Map2k1 or Mek1) and MEK2 (Map2k2 or Mek2) as suppressors of macrophage reparative function (8). Targeting both MEK1 and MEK2 (MEK1/2) using commercially available inhibitor compounds enhanced the ability of macrophages to clear apoptotic polymorphonuclear leukocytes (PMNs) and respond to IL-4/IL-13 (8). Importantly, there was a therapeutic benefit of MEK1/2 inhibition in 2 murine lung injury models: sterile LPS-induced ALI (LPS-ALI) and bacterial pneumonia due to Pseudomonas aeruginosa infection (8,9).…”

“…Targeting both MEK1 and MEK2 (MEK1/2) using commercially available inhibitor compounds enhanced the ability of macrophages to clear apoptotic polymorphonuclear leukocytes (PMNs) and respond to IL-4/IL-13 (8). Importantly, there was a therapeutic benefit of MEK1/2 inhibition in 2 murine lung injury models: sterile LPS-induced ALI (LPS-ALI) and bacterial pneumonia due to Pseudomonas aeruginosa infection (8,9). In these ALI models, mice treated with a MEK1/2 inhibitor compound between 24 and 72 hours after LPS or 48 and 72 hours after bacterial infection experienced improved activity, faster recovery of body weight, reduced pulmonary neutrophilia, and increased macrophage M2 polarization (8,9).…”

“…Importantly, there was a therapeutic benefit of MEK1/2 inhibition in 2 murine lung injury models: sterile LPS-induced ALI (LPS-ALI) and bacterial pneumonia due to Pseudomonas aeruginosa infection (8,9). In these ALI models, mice treated with a MEK1/2 inhibitor compound between 24 and 72 hours after LPS or 48 and 72 hours after bacterial infection experienced improved activity, faster recovery of body weight, reduced pulmonary neutrophilia, and increased macrophage M2 polarization (8,9). Additional studies have demonstrated therapeutic potential of MEK1/2 inhibitors in other murine models of inflammation and infection.…”