Role of Macrophage Receptor with Collagenous Structure in Innate Immune Tolerance

Abstract

Macrophages play a key role in host defense against microbes, in part, through phagocytosis. MARCO (macrophage receptor with collagenous structure) is a scavenger receptor on the cell surface of macrophages that mediates opsonin-independent phagocytosis. The goal of our study is to investigate the role of MARCO in lipopolysaccharide (LPS) or lipotechoic acid (LTA)-induced macrophage tolerance. While it has been established that expression of MARCO and phagocytosis is increased in tolerant macrophages, the transcriptional regulation and biological role of MARCO in tolerant macrophages has not been investigated. Here, we confirm that tolerized mouse bone marrow derived macrophages (BMDM) selectively increase expression of MARCO (both transcript and cell surface receptor) and increase phagocytosis. We found that H3K4me3 dynamic modification of a promoter site of MARCO was increased in tolerized BMDM. Blocking methylation by treatment with 5-Aza-2′-deoxycytidine (5-AZA) resulted in reduced H3K4me3 binding in the promoter of MARCO, decreased expression of MARCO, and impaired phagocytosis in tolerized BMDM. However, 5-AZA had no effect on the inflammatory component of innate immune tolerance. In aggregate, we found that histone methylation was critical to MARCO expression and phagocytosis in tolerized macrophages but did not affect the inflammatory component of innate immune tolerance.

Gene expression differences in adipose tissue associated with breast tumorigenesis

“…Expression of MARCO and corresponding rates of phagocytosis have been found to be increased in immune-tolerant macrophages displaying anti-inflammatory responses. 13 Similarly, VSIG4, which is expressed at 5.72-and 2.85-fold higher levels in tumor adjacent and distant adipose tissues compared with non-malignant adipose, is highly expressed on resting macrophages where it prevents T-cell activation and maintains T-cell tolerance.…”

Targeted immunomodulation using antigen‐conjugated nanoparticles

“…MARCO has been shown to play a role in the clearance of polyanionic substances such as LPS, and the crosslinking of antigen onto the carboxylated particles may provide repeated motifs that solicit engagement by MARCO. In turn, MARCO-mediated endocytosis has been reported to affect innate immune deactivation and tolerance 120 .…”

Coordinated Regulation of miR-155 and miR-146a Genes during Induction of Endotoxin Tolerance in Macrophages

“…Trimethylation of lysine H3K4 marks transcriptionally active genes, whereas trimethylation of lysine H3K9 is associated with transcriptional repression and is generally found in closed inactive chromatin (30)(31)(32). Upon endotoxin tolerance, several genes appear to be regulated at the chromatin level, indicating the presence of an epigenetic mechanism (33)(34)(35)(36). However, no information is yet available on histone modification changes of miRNA genes in the process of endotoxin tolerance.…”