IDDF2024-ABS-0359 Single-cell transcriptomics reveals EGR1 drives the transition of hepatic monocyte-derived macrophages from a pro-inflammatory phenotype to immunosuppressive phenotype to promote chronic infection of HBV

<h3>Background</h3> Macrophages are crucial in managing microbial infections. In the liver, monocyte-derived macrophages (MDMs) constitute the predominant group, representing more than half of all myeloid cells, as revealed by single-cell RNA sequencing (scRNA-seq). Despite their significance, there is still a lack of comprehensive understanding of MDMs biology during CHB. <h3>Methods</h3> scRNA-seq data of liver samples from 23 individuals, including 6 immune tolerant (IT), 5 CHB/immune active (IA), 3 acute resolved (AR), 3 chronic resolved (CR), and 6 HBV-free healthy controls (HC) were downloaded from GSE140228. Gene expression and clinical information of liver biopsy samples from 124 CHB were downloaded from GSE84044. scRNA-seq data processing, cell pseudotime trajectory analysis and cell-cell interaction analysis were performed. <h3>Results</h3> Hepatic MDMs could be classified into CD14_high MDMs, CD14+MDMs and CD16+MDMs based on the expression of CD14 and CD16 (IDDF2024-ABS-0359 Figure 1 (A,B)). Higher frequency of CD14_high MDMs and decreased frequency of CD14+MDMs were found in CHB (IDDF2024-ABS-035 Figure 1 (C)). In CHB, CD16+MDMs mainly diverged towards CD14_high MDMs; while in AR, CR, and HC, CD16+MDMs mainly diverged towards CD14+MDMs (IDDF2024-ABS-0359 Figure 1 (D,E)). A signature score of CD14_high MDMs was significantly associated with ALT, AST, HBV-DNA, Scheuer grade, and Scheuer stage as the higher signature score of CD14_high MDMs, the higher levels of ALT, AST, HBV-DNA, Scheuer grade, and Scheuer stage (IDDF2024-ABS-0359 Figure 2). CD14_high MDMs exhibited anti-inflammatory phenotype and MDSC-like phenotype, with decreased production of IL-1β and TNF-α and with increased expression of TGF-β1 LILRB3, VSIR, and LGALS9 (IDDF2024-ABS-0359 Figure 3). Cell-cell interaction analysis showed that CD14_high MDMs could interact with other immune cells through TGF-β-( TGF-βR1+ TGF-βR2) signaling pathway and LGALS9-CD45 signaling pathway (IDDF2024-ABS-0359 Figure 4). Pseudotime trajectory analysis showed that CD16+MDMs differentiated into CD14_high MDMs, and transcription factors of EGR1 regulated the differentiation (IDDF2024-ABS-0359 Figure 5). <h3>Conclusions</h3> EGR1 drives the transition of hepatic MDMs from a pro-inflammatory phenotype to an anti-inflammatory phenotype to promote the chronic infection of HBV (IDDF2024-ABS-0359 Figure 6).