LRP1-Dependent BMPER Signaling Regulates Lipopolysaccharide-Induced Vascular Inflammation

Abstract

Objective Bacterial endotoxin (lipopolysaccharide, LPS)-mediated sepsis involves dysregulated systemic inflammation, which injures the lung and other organs, often fatally. Vascular endothelial cells act as both targets and mediators of LPS-induced inflammatory responses. Dysfunction of endothelium results in increases of pro-inflammatory cytokine production and permeability leakage. Bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER), an extracellular modulator of BMP signaling, has been identified as a vital component in chronic endothelial inflammatory responses and atherosclerosis. However, it is unclear whether BMPER also regulates inflammatory response in an acute setting such as sepsis. To address this question, we investigated the role of BMPER during LPS-induced acute lung injury. Approach and results Mice missing 1 allele of BMPER (BMPER+/− mice used in the place of BMPER−/− mice that die at birth) were used for LPS challenge. LPS-induced pulmonary inflammation and injury was reduced in BMPER+/− mice as shown by several measures, including survival rate, infiltration of inflammatory cells, edema and production of pro-inflammatory cytokines. Mechanistically, we have demonstrated that BMPER is required and sufficient for the activation of nuclear factor of activated T cells (NFAT) c1. This BMPER-induced NFAT activation is coordinated by multiple signaling pathways, including BMP-independent LRP1-ERK activation, calcineurin signaling and LRP1β-mediated nuclear factor-45 (NF45) nuclear export in response to BMPER treatment. Conclusions We conclude that BMPER plays a pivotal role in pulmonary inflammatory response, which provides new therapeutic options against sepsis shock. The new signaling pathway initiated by BMPER/LRP1 axis broadens our understanding about BMPER’s role in vascular homeostasis.

A self‐organized actomyosin drives multiple intercellular junction disruption and directly promotes neutrophil recruitment in lipopolysaccharide‐induced acute lung injury

“…After 30 min, residual blood was washed out of the lung by PBS infusion. The concentration of lung EBD was measured, as previously described by Lockyer et al (16).…”

Paeonol Attenuates LPS-Induced Endothelial Dysfunction and Apoptosis by Inhibiting BMP4 and TLR4 Signaling Simultaneously but Independently

“…BMP4 is upregulated in the lung during LPS-induced inflammation and in airway epithelial cells treated with either LPS or tumor necrosis factor-a (Li et al, 2014). Furthermore, bone morphogenetic protein-binding endothelial regulator, an extracellular modulator of bone morphogenetic protein signaling, has been identified as a vital component that regulates inflammatory responses in LPS-induced acute lung injury (Lockyer et al, 2017). BMP4 exerts proinflammatory effects resulting in enhanced leukocyte adhesion to the endothelial surface in vitro (Csiszar et al, 2006) and impairs endothelial function, in the mouse aorta, through the accumulation of ROS generated by subunits [nicotinamide adenine dinucleotide phosphate oxidase subunit 1 (NOX1), NOX2, and NOX4] of NADPH oxidase (Miriyala et al, 2006;Csiszar et al, 2007).…”

Loss of Bone Morphogenetic Protein-binding Endothelial Regulator Causes Insulin Resistance

“…Our previous studies [10][11][12][13][14][15] suggest that BMPER is highly expressed in vascular endothelial cells (ECs). To determine whether EC is an important source for BMPER production, we generated endothelium-specific BMPER inducible knockout (eKO) mice by breeding BMPER flox/flox and Cdh5-CreER +/mice.…”

“…BMPER (also called CV-2) binds BMPs and is an extracellular modulator of BMP signaling pathway 9 . We have discovered BMPER plays a pivotal role in BMP-mediated endothelial events and chronic inflammation in the vasculature [10][11][12][13][14][15] . However, the role of BMPER in obesity and insulin resistance has not been studied before.…”