The splice of life: Understanding human macrophage polarization

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Science Translational Medicine  22 Jun 2016:
Vol. 8, Issue 344, pp. 344ec100
DOI: 10.1126/scitranslmed.aag2111

Considered the sentinels of the immune system, ready to respond to any invasion or disturbance, the principal role of macrophages is to defend against exogenous pathogens. However, macrophages can also inappropriately react to self-signals produced during injury or stress and, as a consequence, drive sterile chronic inflammation. They were once thought to be terminally committed and static, with little capacity for altering their phenotype, but we now recognize that macrophages can adopt a range of phenotypes, with proinflammatory M1 macrophages on one end of the spectrum and anti-inflammatory/reparative M2 macrophages at the other. Nevertheless, little is known about the exact mechanisms that instruct macrophage function in these polarized states. Thus, Lin et al. undertook a comprehensive RNA screen to identify alternative splicing (AS) events in human polarized macrophages and gain a better understanding of the protein-coding diversity in macrophage subsets.

AS events are common, observed in more than 90% of multi-exon coding genes and frequently occurring in a cell- and context-specific manner. Surprisingly, Lin et al. found that human M1 polarized macrophages had hundreds of alternatively spliced RNAs, whereas M2 macrophages had very few. The AS events found in M1 and M2 macrophages were largely distinct from those found in circulating hematopoietic cells, indicating that AS activity is specific to the macrophage subsets. Although the study did not include functional verification of the alternatively spliced genes, the authors did demonstrate that induced pluripotent stem cells (iPSCs) can be polarized to the M1 and M2 states and closely model AS differences seen in primary cells, allowing the newly discovered AS events to be probed in more detail in the future.

This study also revealed a probable link between the genetic predisposition to developing cardiometabolic disease and AS activity in inflammatory macrophages. M1 macrophages expressed a large number of alternatively-spliced genes that are predicted to be processed by the splicing factor CELF1, suggesting that inflammatory AS events are coordinated by the activity of the cellular splicing machinery. In addition, a number of these splicing factors, including CELF1, contained single nucleotide polymorphisms (SNPs) in putative transcription factor binding sites that were correlated with cardiometabolic traits. In other words, genetic variants within a promoter region may cause the aberrant activation of splicing factors like CELF1, which could then result in abnormal AS events in carriers of that SNP and influence factors like blood lipids and obesity. Indeed, the authors showed that modifying the amount of CELF1 in M1 macrophages could alter the expression of multiple inflammatory genes. These results link human genetic variation in RNA splicing machinery to differential gene expression and may help identify new causal factors contributing to cardiometabolic diseases.

J. Lin et al., Transcriptome-wide analysis reveals modulation of human macrophage inflammatory phenotype through alternative splicing. Arterioscler. Thromb. Vasc. Biol. 10.1161/ATVBAHA.116.307573 (2016). [Abstract]

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