Macrophage MST1/2 Disruption Impairs Post-Infarction Cardiac Repair via LTB4

Abstract

Rationale: Timely inhibition of inflammation and initiation of resolution are important to repair injured tissues. Mammalian STE20-like protein kinase 1/2 (MST1/2) acts as a regulator of macrophage-associated immune responses to bacterial infections. However, the role of MST1/2 in regulating macrophage phenotype and function in myocardial infarction (MI) remains unclear. Objective: To determine the function and underlying mechanism of macrophage MST1/2 in cardiac repair post-MI. Methods and Results: Using LysMCre-mediated Mst1/2-deficient mice, we found that MST1 deficiency exacerbated cardiac dysfunction after MI. Single-cell RNA sequencing assay indicated that the effect was attributed to a shift of macrophage subtypes from those expressing Cxcl2 and Cd163 toward Ccl2 and Ccl4 expression. Mass spectrometry identified leukotriene B4 (LTB4) as the lipid mediator that was upregulated in the absence of MST1. We found that MST1 phosphorylated 5-lipoxygenase (5-LOX) at its T218 residue, disrupting the interaction between 5-LOX and 5-LOX-activating protein, resulting in a reduction of LTB4 production. In contrast, a 5-LOXT218A variant showed no response to MST1. Moreover, treatment of peritoneal macrophages with LTB4 or medium conditioned by Mst1-deficient macrophages resulted in high Ccl2 and Ccl4 expression and low Cxcl2 and Cd163 expression, except when the cells were co-treated with the LTB4 receptor 1 (BLT1) antagonist CP105696. Furthermore, CP105696 ameliorated cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice and enhanced cardiac repair in wild-type mice treated with XMU-MP-1 after MI. Conclusions: Taken together, our results demonstrate that inhibition of MST1/2 impaired post-MI repair through activating macrophage 5-LOX-LTB4-BLT1 axis.

Identification of 6 cuproptosis- and ferroptosis-related genes linking immune infiltration as diagnostic biomarkers for acute myocardial infarction

“…But another study indicated that upregulated P-STAT3 promotes anti-in ammatory M2 macrophage polarization and protects against AMI [48]. CXCL2, a neutrophil recruiting chemokine, elevated after AMI and involved in the process of in ammation-mediated myocardial injury [49][50][51]. DUSP is known as MAPK phosphatases (MKPs), which can dephosphorylate MAPKs.…”

The Hippo-YAP pathway in various cardiovascular diseases: Focusing on the inflammatory response

“…At a later stage on Days 3 to 7 after MI, anti-inflammatory macrophage subpopulations, which are associated with Arg1 (Arginase 1), are selectively recruited and may participate in the resolution of the postinfarction inflammatory response ( 111 ). The expression of YAP and TAZ was increased in macrophages undergoing proinflammatory or reparative phenotype changes ( 91 ), and the expression of endogenous MST1 in the cardiac macrophages of wild-type mice was decreased in the first 3 days after MI ( 92 ), suggesting the potential role of the Hippo pathway in the cardiac inflammatory response after MI. Genetic deletion of Yap / Taz in macrophages impairs the proinflammatory macrophage phenotype and promotes a reparative macrophage phenotype, which is accompanied by improved post-MI ventricular remodeling and heart function after MI.…”

“…In contrast, MP2 cells had high expression of anti-inflammatory genes such as Cd163 , Cbr2 , and Rgs10 . MP3 cells have mixed properties and express anti-inflammatory ( Slpi and Arg1 ) and proangiogenic ( Cxcl2 ) genes ( 92 ). Although no differences were observed in the numbers of infiltrated macrophages, monocytes, or neutrophils in Mst1/2 myeloid-specific knockout hearts compared to controls, there were differences in the numbers of the three macrophage subtypes, as indicated by increased MP1 cells and decreased MP2 and MP3 cells.…”

“…Although no differences were observed in the numbers of infiltrated macrophages, monocytes, or neutrophils in Mst1/2 myeloid-specific knockout hearts compared to controls, there were differences in the numbers of the three macrophage subtypes, as indicated by increased MP1 cells and decreased MP2 and MP3 cells. In particular, Mst1 mutant hearts showed increased Spp1 expression levels and reduced Cd163 and Arg1 expression in CD68 + cells, indicating that Mst1/2 knockout promoted macrophage subtype switching and impaired inflammation resolution in the mouse hearts after MI ( 92 ). Mechanistically, MST1 phosphorylates 5-lipoxygenase at its T218 residue, resulting in a reduction of leukotriene B4 production.…”

Mechanosensing in macrophages and dendritic cells in steady-state and disease

“…In macrophages, deficiency in Mst1/2 worsens cardiac dysfunction after myocardial infarction, as mice lacking Mst1/2 in their macrophages exhibited a marked increase in left ventricular end-diastolic and end-systolic volume and decrease in ejection fraction and fractional shortening ( Liu et al, 2021 ). In addition, the pharmacological inhibition of YAP/TAZ dampened pro-inflammatory gene expression (IL-1β and IL-12β) ( Mia et al, 2020 ).…”