Macrophages reducing inflammation when they engulf cellular debris or foreign microbes that contribute to inflammation

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Researchers at the University of Illinois at Chicago have identified a molecular switch that causes immune cells called macrophages to clean up cellular debris caused by infections instead of contributing to inflammation and tissue injury.

Their findings are reported in the journal Proceedings of the National Academy of Sciences.

Macrophages are a type of immune cell found throughout the body.

These cells can produce inflammation, which is good in moderation because inflammatory signals bring other immune cells to a specific location to clear an infection.

However, when inflammation gets out of control, as it can in cases of inflammatory diseases, it can cause excess cellular and tissue damage, contributing to a vicious cycle that is very difficult to reverse.

But macrophages also play a significant role in reducing inflammation when they engulf cellular debris or foreign microbes that contribute to inflammation.

The mechanism behind macrophages‘ ability to switch back and forth between these two diametrically opposed roles has long-puzzled scientists.

Researchers led by Saroj Nepal, research assistant professor in the department of pharmacology at the UIC College of Medicine, have found that a molecule called Gas6 is required to induce macrophages to perform their anti-inflammatory role by engulfing and digesting cellular debris that can contribute to inflammation.

The molecule could serve as a potential drug target for drug makers interested in coaxing the cells toward their anti-inflammatory state to help treat people.

In a mouse model of acute lung injury, Nepal and colleagues found that lung macrophages expressed both inflammatory and anti-inflammatory proteins.

One of the anti-inflammatory proteins was Gas6.

In a mouse model of acute lung injury where the animals’ macrophages were artificially depleted of Gas6, clearance of inflammatory molecules and proteins in the lungs was severely impaired, and the inflammation could not be resolved.

When they artificially boosted levels of Gas6 in the mouse macrophages, inflammation was resolved much faster than in mice with normal macrophages.

“Harnessing the anti-inflammatory function of macrophages using the Gas6 switch holds great potential for treating diseases ranging from heart disease to cancer to rheumatoid arthritis, where inflammation is a key underlying feature,” Nepal said.


Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation.

How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown.

Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source.

Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis.

Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis.

These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

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Despite improvements in treatment, cardiovascular disease (CVD) remains the leading cause of death worldwide.

The main cause is atherosclerosis, the pathological process underlying stroke, coronary artery disease (CAD), and peripheral vascular disease.

Cells of the myeloid lineage, particularly monocyte/macrophages, play a pivotal role in atherogenesis, which is triggered by an inflammatory response to lipoproteins that are modified in the vessel wall.

Here, innate responses initiate the recruitment, homing, migration, and differentiation of monocytes into macrophages, where they orchestrate a plethora of functions including phagocytosis, efferocytosis, proliferation, migration, secretion of inflammatory molecules (e.g., tumor necrosis factor alpha [TNF-α]), production of resolving molecules (e.g., interleukin [IL]-10), and cell death.

In mature lesions, failure of macrophage resolution mechanisms and the subsequent increased immune response may underlie processes that exacerbate disease (Tabas, 2010).

TNF-related apoptosis-inducing ligand (TRAIL) was originally identified as a cancer-killing cytokine, but over the last 10 years it has become clear that TRAIL has pleiotropic functions beyond killing and can modulate multiple cellular processes, including proliferation, migration, and differentiation (Harith et al., 2013, Kavurma and Bennett, 2008, Kavurma et al., 2008b, Manuneedhi Cholan et al., 2017). Our particular interest is its role in CVD.

In humans, low plasma TRAIL levels independently predict cardiovascular events and mortality (Volpato et al., 2011), and TRAIL is reduced in the circulation of patients with CVD (Schoppet et al., 2006), suggesting a protective role.

The recent identification of 11 loss-of-function TRAIL single-nucleotide polymorphisms (SNPs) that confer increased risk of carotid artery atherosclerosis supports this view (Pott et al., 2017). We and others identified TRAIL’s non-apoptotic functions in the vasculature, including in neointimal thickening, angiogenesis, and peripheral vascular disease, and in advanced atherosclerosis (Chan et al., 2010, Di Bartolo et al., 2011, Di Bartolo et al., 2013, Di Bartolo et al., 2015, Kavurma et al., 2008a, Secchiero et al., 2004a, Secchiero et al., 2006).

Our atherosclerotic murine models lacking TRAIL corroborate the human association studies. For example, high-fat diet (HFD)-fed Trail−/−Apoe−/− mice exhibited 150% larger plaques than Apoe−/− mice (Di Bartolo et al., 2011). Intriguingly, these mice not only had significantly more monocyte/macrophages in their plaques but also increased monocyte/macrophage numbers in kidney (Cartland et al., 2014) and pancreata (Di Bartolo et al., 2011), suggesting that TRAIL may control macrophage accumulation in injured tissues.

In contrast to our observations, TRAIL administration to diabetic Apoe−/− mice attenuated atherosclerosis, in part, by inducing macrophage death (Secchiero et al., 2006).

Thus, the role of TRAIL in monocyte/macrophage function is unclear. Here we examined samples from patients with CAD and several murine models of atherosclerosis, as well as monocyte/macrophages in vitro. We identified an iNOShiTRAIL+ macrophage population that appeared critical in resolving atherosclerosis. Furthermore, we describe a unique anti-inflammatory pathway, the IL-18-TRAIL axis, in patients with CAD. These findings suggest that TRAIL is critical in modulating atherogenesis and has wider implications in mechanisms regulating inflammation.


More information: Saroj Nepal et al. STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1821601116

Journal information: Proceedings of the National Academy of Sciences
Provided by University of Illinois at Chicago

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