Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair

Abstract

Rationale: Macrophages are critically involved in wound healing following myocardial infarction (MI). Lgr4, a member of leucine-rich repeat-containing G protein-coupled receptor (LGR) family, is emerging as a regulator of macrophage-associated immune responses. However, the contribution of Lgr4 to macrophage phenotype and function in the context of MI remains unclear. Objective: To determine the role of macrophage Lgr4 in MI and to dissect the underlying mechanisms. Methods and Results: During early inflammatory phase of MI, infarct macrophages rather than neutrophils expressed high level of Lgr4. Macrophage-specific Lgr4 knockout mice (Mac-L4KO) had no baseline cardiovascular defects but manifested improved heart function, modestly reduced infarct size, decreased early mortality due to cardiac rupture, and ameliorated adverse remodeling after MI. Improved outcomes in Mac-L4KO mice subjected to MI were associated with mitigated ischemic injury and optimal infarct healing, as determined by reduction of cardiac apoptosis in the peri-infarct zone, attenuation of local myocardial inflammatory response, decrease of matrix metalloproteinase expression in the infarct, enhancement of angiogenesis, myofibroblast proliferation, and collagen I deposition in reparative granulation tissue as well as formation of collagen-rich scar. More importantly, Mac-L4KO infarcts had reduced numbers of infiltrating leukocytes and inflammatory macrophages but harbored abundant reparative macrophage subsets. Lgr4-null infarct macrophages exhibited a less inflammatory transcriptional signature. These findings were further supported by transcriptomic profiling data showing repression of multiple pathways and broad-spectrum genes associated with pro-inflammatory responses in Mac-L4KO infarcts. Notably, we discovered that Lgr4-mediated functional phenotype programing in infarct macrophages was at least partly attributed to regulation of activator protein (AP)-1 activity. We further demonstrated that the synergistic effects of Lgr4 on AP-1 activation in inflammatory macrophages occurred via enhancing cAMP response element-binding protein (CREB)-mediated c-Fos, Fosl1, and Fosb transactivation. Conclusions: Together, our data highlight the significance of Lgr4 in governing pro-inflammatory phenotype of infarct macrophages and post-infarction repair.

Fosl1 Targets AMPK to Inhibit Autophagy-Mediated Anti-Apoptotic and Anti-Inflammatory Effects in Spinal Cord Injury

“…Although Fosl1 is well-known as an essential transcription factor that constitutes the AP-1 compound with c-fos and c-jun in the development of many diseases of injury [24,[53][54][55], its role in the occurrence and progression of SCI has not yet been elucidated. By exploring the GSE45006 and analyzing the datasets, we learned that Fosl1 expression was signi cantly upregulated following SCI at 1 d and 3 d postoperation.…”

Lgr4 promotes aerobic glycolysis and differentiation in osteoblasts via the canonical Wnt/β-catenin pathway

“…Osteocalcin‐Cre (Ocn‐Cre) C57BL/6 mouse line used in the current study has been described ( 30,31 ) and was purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Lgr4 flox/flox mice were generated as described ( 18,32,33 ) and were backcrossed with C57BL/6 mice for at least nine generations to obtain a pure C57BL/6 background. Mice were housed in a specific pathogen‐free environment with a constant temperature (22 ± 2°C) and humidity (50–70%), and a fixed light cycle.…”

The Role of LGR4 (GPR48) in Normal and Cancer Processes

“…It has also been shown that LGR4, rather than LGR5, is indispensable in mammalian early hematopoiesis by downstream TGF-beta signaling [ 93 ]. In addition, LGR4 may play a critical role in wound healing, fibrosis, and inflammation [ 94 , 95 ], particularly through the NF-κB signaling [ 33 , 96 ]. LGR4 also takes part in the innate immune response by modulating the TLR2/4 pathway and regulating monocyte to macrophage differentiation [ 97 , 98 ].…”