Scientists in recent years have grown impatient with the conventional model of macrophage activation. According to this model, macrophages—the scavenger cells that engulf and cellular debris and pathogens—are divided into two groups: “classical macrophages,” which spur on inflammatory processes, and “alternative macrophages” which shut down inflammation. And yet macrophages, in respond to environmental cues, are capable of altering their physiology, giving rise to different populations of cells with distinct functions. Functionally, macrophages even seem to display mixed types, as though their activation pathways were as varied as the colors of an artist’s palette.
Still, the old model prevailed. It proved too useful to alter, especially since new information about macrophage activation was emerging slowly and seemed more suggestive than definitive. Phenotypic analysis, for example, did little to induce change. And even microarray-based gene expression profiling fell short, despite linking macrophage plasticity to changes in transcriptional regulation. With this technique, it was possible to collect evidence of transcriptional reprogramming, but it was still a challenge to sort through the molecular mechanisms that might be at work.
Undeterred, researchers began studying macrophage activation more systematically. In particular, a group of researchers at the University of Bonn recently expressed an interest in undertaking an integrative analysis of epigenomic and transcriptomic data to better understand how macrophages respond to environmental cues. The researchers’ ultimate goal was to identify specific transcription factor combinations responsible for cellular macrophage programs.
Considerable progress toward this goal was reported February 13 in Immunity, in a paper entitled “Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation.” The paper’s authors include scientists from the University of Bonn, as well as colleagues from the University of Massachusetts and the University of Edinburgh. In their paper, they go so far as to propose a “refined, activation-independent core signature for human and murine macrophages.”
According to these researchers, macrophages are capable of processing diverse stimuli, which activate specific transcriptional programs. Further, these programs drive macrophages to fates more varied than the two in the traditional macrophage activation model. In fact, macrophages may assume at least nine different forms which use their weapons to optimally fight intruders in different ways.
To uncover these results, the researchers stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analyzing this data, the researchers determined that NFKB1, JUNB, and CREB1 are central transcription factors of macrophage activation. In addition, they found that TNF, PGE2, and P3C activates a STAT4-associated transcriptional program.
Essentially, they identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. “With complex bioinformatic analyses, we obtained a type of fingerprint for each macrophage which showed us which genes in the cell were directly active,” said Prof. Dr. med. Joachim L. Schultze from the Life & Medical Sciences (LIMES) Institute of the University of Bonn. Using this genetic fingerprint, the scientists were able to deduce which combination of stimuli led to the macrophage developing in a particular direction.
Applying their newfound knowledge, the researchers examined how transcriptional processes differ between alveolar macrophages from smokers and those from patients with chronic obstructive pulmonary disease (COPD). Curiously, the researchers found a loss of inflammatory signatures in COPD patients.
Prof. Schultze said, “We have to step away from the simple classification of macrophages and investigate them more closely in respective connections with diseases.” Once scientists “depart from the conventional pattern, fully new concepts [will] open up.”
“This is the dawn of new therapy options,” added Prof. Schultze, noting that macrophages play a role in many widespread diseases such as arteriosclerosis, obesity, diabetes, asthma, Alzheimer’s disease, and cancer.