Myeloid‐Mas Signaling Modulates Pathogenic Crosstalk among MYC⁺CD63⁺Endothelial Cells, MMP12⁺Macrophages, and Monocytes in Acetaminophen‐Induced Liver Injury

Abstract

Acetaminophen overdose is a leading cause of acute liver failure (ALF). Despite the pivotal role of the inflammatory microenvironment in the progression of advanced acetaminophen‐induced liver injury (AILI), a comprehensive understanding of the underlying cellular interactions and molecular mechanisms remains elusive. Mas is a G protein‐coupled receptor highly expressed by myeloid cells; however, its role in the AILI microenvironment remains to be elucidated. A multidimensional approach, including single‐cell RNA sequencing, spatial transcriptomics, and hour‐long intravital imaging, is employed to characterize the microenvironment in Mas1 deficient mice at the systemic and cell‐specific levels. The characteristic landscape of mouse AILI models involves reciprocal cellular communication among MYC+CD63+ endothelial cells, MMP12+ macrophages, and monocytes, which is maintained by enhanced glycolysis and the NF‐κB/TNF‐α signaling pathway due to myeloid‐Mas deficiency. Importantly, the pathogenic microenvironment is delineated in samples obtained from patients with ALF, demonstrating its clinical relevance. In summary, these findings greatly enhance the understanding of the microenvironment in advanced AILI and offer potential avenues for patient stratification and identification of novel therapeutic targets.

Efficient high-resolution fluorescence projection imaging over an extended depth of field through optical hardware and deep learning optimizations

“…Fluorescence microscopy is widely used for immune observations [ 36 – 38 ], but it faces challenges from the heterogeneity and autofluorescence of thick organs. To overcome these challenges, we propose deep focus microscopy based on the LFM setup, which captures the spatial-angular measurements that separate the signal and background from different angles.…”