New study on the role of macrophages beyond inflammation published in Nature Metabolism

Myriam Aouadi PhD (right) Group Leader Integrated Cardio Metabolic Center, Department of Medicine, Huddinge, Karolinska Institutet and Cecilia Morgantini MD,PhD (left) Postdoctoral associate in the Aouadi lab Medical Fellow in the Unit of Endocrinology at the Karolinska Hospital recently published a study in Nature Metabolism. The study was done in collaboration with scientists from AstraZeneca.

Synopsis

With obesity affecting 600 million adults worldwide and the inefficiency of current therapies to stop the rapidly rising prevalence of its associated metabolic diseases such as Type 2 Diabetes, there is a pressing need to better understand these diseases and to develop new therapeutic strategies. In Sweden, 50% of the population is overweight or obese according to the Swedish health agency.

In obesity, the inability of adipose tissue to store excess nutrients in forms of fat leads to the ectopic deposition of lipids in non-adipose tissue such as liver. This excessive lipid accumulation in the liver, called hepatic steatosis or non-alcoholic fatty liver disease (NAFLD), is highly associated with liver metabolic dysfunction. Considering the important role of the liver in the regulation of lipid and glucose metabolism, hepatic steatosis can have a large impact on whole body metabolism and therefore contribute to metabolic diseases, such as Type 2 Diabetes.

The role of liver inflammation in the development of metabolic disease has been a subject of debate for many years. Macrophages are cells of the immune system that play an important role in defending the body against pathogens. However, they have been recently described as key players in the development of metabolic diseases. Macrophages are present throughout the body and they represent the highest proportion of immune cells in the liver. Our current knowledge of liver macrophages is limited due to studies using non-specific transgenic models, depletion methods or whole liver transcriptomic analyses.

Unfortunately, this gap in our knowledge of liver macrophage biology has led to the assumption that liver macrophages undergo a pro-inflammatory activation resulting in the excessive production of inflammatory factors that contribute to obesity-induced insulin resistance. This dogma has motivated research groups to explore anti-inflammatory drugs as potential therapies for metabolic diseases. In their study recently published in Nature Metabolism, Morgantini et al. made the observation that liver macrophages actually do not become inflammatory with obesity and insulin resistance in three species, Drosophila, mice and humans. Using particular methods for macrophage isolation combined with next generation sequencing, they found that the transcriptomic profile of liver macrophages is dramatically affected by obesity but independently of their inflammatory status. "These unexpected findings shifted the paradigm describing inflammatory macrophages and inflammation as drivers of hepatic metabolic disease," says lead author Cecilia Morgantini.

To elucidate the mechanism whereby liver macrophages could regulate hepatic metabolism, Cecilia Morgantini et al. used a patented technology developed by Myriam Aouadi to deliver siRNA and silence genes in macrophages in a cell- and tissue-specific manner. Using this unique technology, they described a novel mechanism through which macrophages can impair liver metabolism and promote insulin resistance through secretion of non-inflammatory factors, such as Igfbp7. "It was fascinating to observe a conserved mechanism whereby IGFBP7 produced by liver macrophages in mice and hemocytes in Drosophila could regulate glucose and lipid metabolism", says Myriam Aouadi, PI of the project.

In human they discovered an evolutionary regulatory mechanism whereby IGFBP7 undergoes RNA editing at a higher frequency in obese patients with metabolic disease. This RNA editing event, which only occurs in humans but not in mice or Drosophila, leads to the generation of a new isoform of IGFBP7 with protective properties. "Our study reveals a previously unknown role of macrophages beyond inflammation and opens up a new avenue for research in the field of immunometabolism and the development of new therapeutic strategies for metabolic and associated liver diseases. We are now investigating the many roles of macrophages and their involvement in liver disease. This is a really exciting time as we will now uncover new biological function of macrophages about a hundred years after they were discovered,” says Myriam Aouadi.

Graphical Abstract

In mouse, in insulin sensitive condition: IGFBP7 produced by liver macrophages binds the hepatic insulin receptor IR and enhances AKT activation by insulin; in insulin resistant condition, in which AKT does not respond to insulin, IGFBP7 binds the IR with less affinity but can still activate the ERK pathway and induce gluconeogenesis and lipogenesis. In human, edIGFBP7 is more frequent in the insulin resistant state. EdIGFBP7 has a higher capacity to bind the IR and activate AKT compared to wtIGFBP7. IR: insulin receptor. ed: edited; wt wild type.

Bullet points

• Liver macrophages do not become inflammatory activated in obesity and insulin resistance in drosophila, mice and humans.
• Liver macrophages produce non-inflammatory factors, such as IGFBP7, that directly regulate liver metabolism.
• IGFBP7 expressed by liver macrophages in human, but not mice, undergoes RNA editing at a high frequency in obese insulin resistant patients.
• The RNA editing of IGFBP7 in human liver macrophages leads to the production of a new and protective isoform with a higher capacity to induce the insulin signaling pathway.

Image: Liver RNA in situ hybridization Image displaying Igfbp7 (green) in liver macrophages, identified with the marker Emr1 (F4/80) and DAPI. Right Image: Endogenous expression of the Igfbp7 homolog (Impl2) in hemocytes (macrophages) in Drosophila.