Tag Archives: Macrophage

Our white blood cells could be ‘reprogrammed’ to lower inflammation on demand

White blood cells receive ‘orders’ from our bodies to cause or subdue inflammation, a new paper reports, as a natural part of the immune response.

A mouse macrophage engulfing two particles at the same time (unrelated to the study).
Image via Wikimedia.

They argue that this effect can be used to prevent Acute Respiratory Distress Syndrome (ARDS), which affects some COVID-19 patients. ARDS is a type of respiratory failure caused by a buildup of fluid in the lungs.

Pimp my immune response

“We found that macrophage programming is driven by more than the immune system — it is also driven by the environment in which the macrophages reside,” said lead author Asrar Malik, the Schweppe Family Distinguished Professor and head of pharmacology and regenerative medicine at the University of Illinois at Chicago (UIC).

Macrophages are those immune cells that find a threat, wrap around it, and start digesting it. However, the new findings showcase that they also play a part in controlling inflammation. While a natural part of our bodies’ efforts against infection, and quite effective against them, excessive or prolonged inflammation can also damage our own tissues and organs.

In essence, these cells both cause and keep inflammation in check. The team analyzed how they determine which of the two approaches they use at any given time using mice. Their goal was to help patients suffering from excessive inflammation and conditions such as ARDS while infected with the coronavirus.

“We demonstrated that lung endothelial cells — which are the cells that line blood vessels — are essential in programming macrophages with potent tissue-reparative and anti-inflammatory functions,” said Dr. Jalees Rehman, UIC professor of medicine and pharmacology and regenerative medicine and co-lead author of the paper.

The researchers found that one protein, R-spondin-3, was present in high levels in the blood during injury and inflammation. The next step was to genetically-engineer lab mice to lack this protein in these cells — which led to the macrophages no longer dampening inflammation.

“Instead, the lungs became more injured,” said Bisheng Zhou, UIC research assistant professor of pharmacology and regenerative medicine and first author of the study. “We tried this in multiple models of inflammatory lung injury and found consistent results, suggesting that blood vessels play an important instructive role in guiding the programming of macrophages.”

The findings point the way towards a promising avenue of treatment for ARDS, but could also help us understand why some patients have better outcomes after a COVID-19 infection than others. Our own immune response has been shown to cause an important part of the damage associated with this disease. Poor vascular health or other underlying conditions that affect our blood vessels could impact our recovery, the team believes.

While the study only worked with lung tissue, it’s likely that those in other organs would show the same mechanisms, according to the authors.

The paper “The angiocrine Rspondin3 instructs interstitial macrophage transition via metabolic–epigenetic reprogramming and resolves inflammatory injury” has been published in the journal Nature Immunology.

tattoo

New insight into what makes tattoos last forever could improve laser removal techniques

Once you get inked, you’re in it for life. Behind the scenes, however, to have a tattoo last forever, the cells that carry the pigment die and pass on their ink, in a continuous cycle. New findings could lead to better tattoo removal techniques that leave the skin more natural looking.

tattoo

Credit: Pixabay.

Until not too long ago, scientists used to think that tattoos lingered on the skin by staining fibroblast cells, which are the most common cells of connective tissue in the dermal layers of animals. However, we now know that it’s not only skin cells that get inked but also macrophages — specialized immune cells that are called to the wound site and then engulf the tattoo pigment like they would normally do with any invading foreign organism or dying cell. Most of the fibroblasts, and macrophages alike, become suspended in the dermis where they’re locked permanently. The dye in both cells shows through the dermis which is how you can see your tattoo.

Sandrine Henri and Bernard Malissen, both researchers at the Centre d’Immunologie de Marseille-Luminy, have found that the full picture is even more complex. It was always assumed that the macrophages carrying pigments live forever, which is what allows the tattoo to be permanent. What the French researchers found, however, was that the macrophages do die eventually, only to pass on their pigment to other cells that keep carrying the torch.

We  were quite surprised to see that only very limited infos were available on the skin cells that are responsible for tattoo persistence and that  account for their strenuous removal. Therefore the knowledge we recently gained on the immunobiology of skin macrophages, their dynamics and the possibility to ablate them ‘à la carte’ explain why we are getting a greater understanding of their permanence,” Malissen said.

In one experiment, the researchers genetically engineered a mouse in which they were able to kill the macrophages circulating in the dermis and other tissues. Over weeks, new macrophages derived from monocytes (precursor cells) moved into the area. Only the dermal macrophages could gobble up the pigment, the researcher found in a trial when they tattooed the tail of the mouse.

Because tattoo pigment can be recaptured by new macrophages, a tattoo appears the same before (left) and after (right) dermal macrophages are killed. Credit: Baranska et al., 2018.

Because tattoo pigment can be recaptured by new macrophages, a tattoo appears the same before (left) and after (right) dermal macrophages are killed. Credit: Baranska et al., 2018.

The tattoo’s appearance did not change when the macrophages were destroyed en masse. Upon closer investigation, the scientists found that the dead macrophages release their pigment into the surroundings, which is eventually absorbed by the monocyte-derived macrophages before the pigment has a chance to disperse.

This pigment capture, release, and recapture cycle occurs over and over again in tattooed skin, whether or not macrophages are killed off in one single burst. When researchers transferred a piece of tattooed skin from one mouse to another, the pigment-carrying macrophages were sourced from the recipient, rather than the donor animal, over several weeks.

Green tattoo pigment is absorbed by macrophages (left). Pigments is released when macrophages die (center). About 90 days later, the pigment is gobbled up by new macrophages (right). Credit: Baranska et al., 2018.

Green tattoo pigment is absorbed by macrophages (left). Pigments is released when macrophages die (center). About 90 days later, the pigment is gobbled up by new macrophages (right). Credit: Baranska et al., 2018.

The findings could one day lead to tattoo removal procedures that are more efficient and less painful. When a tattoo is no longer desired, people typically turn to laser removal. Laser pulses fragment the tattoo pigments, flushing them into the body’s lymphatic system. The procedure isn’t perfect, though, as several cycles of treatment are required and some parts of tattoos remain immune to the procedure. We now know this happens because a fraction of the fragmented pigments remain on site and get recaptured by neighboring macrophages.

“Tattoo removal can be likely improved by combining laser surgery with the transient ablation of the macrophages present in the tattoo area,” Malissen told ZME Science. “As a result, the fragmented pigment particles generated using laser pulses will not be immediately recaptured, a condition increasing the probability of having them drained away via the lymphatic vessels.”

Malissen says that, unfortunately, the study’s findings won’t do anything to stop tattoo fading, which is “likely due to the fact that during the successive capture-release-capture cycles, minute amounts of released pigments are drained away from the skin.” Beyond tattoos, the study aids people with hyperpigmentation conditions in which patches of skin become darker in color than the normal surrounding skin.

Findings appeared in the Journal of Experimental Medicine.

 

Cross section of newborn mouse's testis (Ø = 20 µm), where we can see the seminiferous tubules (red) surrounded by macrophages (green). Confocal micrograph. © Noushine Mossadegh-Keller and Sébastien Mailfert / CIML

New insights into testicular macrophages, the guardians of male fertility

Two types of testicular macrophage — important cells of the immune system — have been described in great detail by French researchers at the Centre d’Immunologie de Marseille-Luminy. These specialized cells that recognize, engulf and destroy target cells are believed to act like a sort of guardians of fertility. As such, this effort will help us better understand what causes male infertility and might lead to innovative treatments.

Cross section of newborn mouse's testis (Ø = 20 µm), where we can see the seminiferous tubules (red) surrounded by macrophages (green). Confocal micrograph. © Noushine Mossadegh-Keller and Sébastien Mailfert / CIML

Cross section of newborn mouse’s testis (Ø = 20 µm), where we can see the seminiferous tubules (red) surrounded by macrophages (green). Confocal micrograph. © Noushine Mossadegh-Keller and Sébastien Mailfert / CIML

Our immune system is critical to our survival. This is why AIDS is such a terrible disease — it’s not the infection itself that kills you but everything else that would normally fly by since the immune system is now superseded. Its primary role is to 1) distinguish native cells and 2) identify, then seek and destroy potentially pathogen foreign cells.

Meet the sperm guard

Technically, though, spermatozoa are also foreign cells. It can take at least a dozen years before puberty sets in and sperm is finally produced by the male testis. Typically, the sperm should be identified as an intruder by certain immune system elements and destroyed. Obviously, this doesn’t happen otherwise there would be no more babies in the world, or you and me for that matter.

This is where the testicular macrophages come in. A macrophage is a large white blood cell which gobbles foreign pathogens like bacteria. Not only do they act as antimicrobial warriors, they also play critical roles in immune regulation and wound-healing. Macrophages exist in nearly all tissues and are produced when white blood cells called monocytes leave the blood and differentiate in a tissue-specific manner. Depending on where they’re made and where they function, macrophages come in different types and bear different names. For example, macrophages present in the brain are termed microglia and in the liver sinusoids they are called Kupffer cells.

In human male testicles, scientists have identified two types of macrophages, each originating in one of the two compartments of the testis. In the so-called interstitial space, where we can find the testosterone-producing Leydig cells, one type of interstitial macrophages is produced. These are made from embryonic cells and are present from the beginning of an individual’s life. The other kind of macrophage is peritubular, named so because we can find it on the surface of seminiferous tubules that house sperm cell precursors.

Studying mice, the French researchers led by Michael Sieweke found peritubular macrophages only appear two weeks after the mice were born, which coincides with the rodent’s puberty. After puberty sets in, the peritubular macrophages stay with them for the rest of their lives, as reported in the Journal of Experimental Medicine.

“We show that embryonic progenitors give rise to the interstitial macrophage population, whereas peritubular macrophages are exclusively seeded postnatally in the prepuberty period from bone marrow (BM)–derived progenitors. As the proliferative capacity of interstitial macrophages declines, BM progenitors also contribute to this population. Once established, both the peritubular and interstitial macrophage populations exhibit a long life span and a low turnover in the steady state,” the authors wrote.

Sieweke’s team now wants to focus on the relationship between macrophages, sperm, and testosterone production. This investigation might one day enable innovative treatments for certain kinds of male infertility.

Atrioventricular node with macrophages.

Macrophages conduct electricity through the heart to keep it beating properly

Macrophages seem to not only help keep the body safe and clean but also make sure it stays very much alive by helping the mammalian heart beat in rhythm, new research reveals.

Colorized scanning electron micrograph of a macrophage.
Image credits NIAID / Flickr.

They’re the champion eaters of our bodies, gulping up pathogens and waste wherever they find them — they’re the macrophages. These white cells play a central part in our immune systems, for which we’re all thankful. But they may play a much more immediately vital role for us than we’ve suspected. Researchers from the Massachusetts General Hospital have discovered that these cells play a central part in regulating cardiac activity by conducting electrical signals through the heart.

“This work opens up a completely new view on electrophysiology; now, we have a new cell type on the map that is involved in conduction,” says senior author Matthias Nahrendorf, a systems biologist at Massachusetts General Hospital, Harvard Medical School.

“Macrophages are famous for sensing their environment and changing their phenotype very drastically, so you can think about a situation where there is inflammation in the heart that may alter conduction, and we now need to look at whether these cells are causally involved in conduction abnormalities.”

Researchers have known for some time now that macrophages can be found in and around hearts battling an infection — cause that’s what they do. But Nahrendorf team found that they still hang around in healthy hearts, in much greater numbers than would be required for simple maintenance or defense. So he and his team set out to understand why.

After performing MRI and electrocardiogram studies on model depleted of macrophages, the team found that the heart was arrhythmic and beat too slowly. By analyzing the heart tissue of a healthy mouse, they found that there’s a high density of macrophage cells at atrioventricular node, which carries electricity from the atria to the heart’s ventricles.

Working with David Milan and Patrick Ellinor, both electrophysiologists at Massachusetts General Hospital, the researchers found that the macrophages extend their membranes between cardiac cells and create pores, known as gap junctions, for electricity to flow through. This helps prepare the heart’s conducting cells (the ‘wiring’) for the next burst of electricity — allowing them to maintain a fast contraction rhythm.

Atrioventricular node with macrophages.

Cardiomyocytes (heart muscle cell, red) densely interspersed with macrophages (green).
Image credits Maarten Hulsmans / Matthias Nahrendorf.

“When we got the first patch clamp data that showed the macrophages in contact with cardiomyoctes were rhythmically depolarizing, that was the moment I realized they weren’t insulating, but actually helping to conduct,” Nahrendorf says.

“This work was very exciting because it was an example of how team science can help to connect fields that are traditionally separated — in this case, immunology and electrophysiology.”

The researchers say that the next step is to see whether macrophages have a hand to play in common conduction abnormalities in the heart. There are potential ties between macrophages and anti-inflammatory drugs, which are widely reported to help with heart disease. If macrophages do play a role in disease, the researchers say it can open up a new line of therapeutics, as these immune cells naturally consume foreign molecules in their presence and are easy to target as a result.

The full paper “Macrophages Facilitate Electrical Conduction in the Heart” has been published in the journal Cell.