Immune
Cell Assassins Reveal Their Nurturing Side
Don’t be misled by the
bloodthirsty names of immune cells. Mounting research shows that the cells also
fine-tune tissues and help the body heal.
[[Everything is always much more
complicated than we thought.]]
Macrophages and
other cells of the immune system are known as destroyers of bacteria and other
pathogens. But research is finding that they also have important jobs in
healing and molding the body.
February 11, 2020
After a heart attack,
patients are increasingly often offered the option of stem cell therapy, in
which stem cells from their bone marrow are injected into the heart to
help it heal. Skeptics, however, point out that solid evidence of the therapy’s
benefits is lacking: It’s worked modestly in some animal studies, but its
effectiveness is uncertain, and scientists have only been able to guess at how
it helps if it does.
Last November, a team of
cardiologists set out to provide some clarity on this controversial treatment.
Instead, their work found evidence that some immune
system cells play a nurturing, healing role that is far removed from
their familiar calling as bloodthirsty protectors of the body.
Scientists and doctors from
Cincinnati Children’s Hospital led by Jeffery Molkentin first injected stem cells into mice
whose hearts had been temporarily deprived of oxygen to mimic a heart attack.
Their hearts showed some transient inflammation from the injections, but the
mice healed mildly better than those that received a placebo. Still, it
was possible that the inflammation, rather than the stem cells, contributed to
the improvement: “Any good immunologist will tell you, you need an inflammatory
response to get healing,” said Molkentin.
To find out, the team injected a
second set of heart-damaged mice with zymosan, a chemical that induces
inflammation, instead of stem cells — and they saw the same improvement in
heart function. Finally, they injected only bits and pieces of dead cells,
which would do nothing more than prompt the immune system to infiltrate the
tissue and clean up the debris. Even this, they found, improved heart function.
The protective benefit of the
treatment didn’t come from a regenerative effect of the stem cells, the
researchers realized. It came instead from the inflammatory immune response,
which seemed to set up what Molkentin calls “a second wave of healing.”
Molkentin’s study is the latest
in an avalanche of papers over the last decade showing that certain immune
cells moonlight in roles unrelated to fighting disease. The phenomenon is not
limited to the heart. These immune cells, many of which reside permanently in
specific tissues, have been identified as participants in a range of biological
activities, including heartbeat regulation, the stabilization of pregnancy, and
even brain development.
More Than Elite Assassins
Immune system nomenclature is
rife with cell labels suitable for fierce, battle-ready warriors. The Greek
name “macrophage,” for example, translates as “big eater” and evokes images of
ravenous, rotund cells gobbling up the bits of debris floating around them.
“Natural killer” (NK) lymphocytes sound like elite assassins sailing through
the bloodstream, breezily picking off disease-causing cells.
“When the names were given to
immune cells, it was always in the context of what they did to protect us,”
said Muzlifah Haniffa, an immunologist and single-cell genomics
researcher at Newcastle University. Haniffa recently published an atlas of the
developing blood production system in the human fetus as part of the Human Cell Atlas project,
which aims to develop a comprehensive map that catalogs
every type of cell in the human body. She believes that the names we
gave immune cells may have pigeonholed them and prevented us from understanding
their full range of abilities.
Muzlifah
Haniffa, an immunologist and single-cell genomics researcher at Newcastle
University, found evidence of immune cells’ versatility while she was working
on the Human Cell Atlas project. Here, she is isolating immune cells from human
blood.
Jooney Woodward, Wellcome CC-BY
Consider the macrophage. It is a
type of phagocyte — literally an “eating cell” — described and named in
1882 by the Russian biologist Elie Metchnikoff. Metchnikoff had a hunch that
starfish could rid themselves of foreign bodies, so as an experiment, he
inserted a rose thorn into a transparent starfish larva. Peering through the
primitive microscope on his desk, he watched as hungry phagocytic cells
lumbered toward the thorn, surrounded it and gobbled it up.
Metchnikoff didn’t immediately
assume that these phagocytes are specialized for disease fighting and pathogen
removal alone. Trained as an evolutionary biologist, he knew that simple
organisms generally had relatively unspecialized cells. He therefore
hypothesized that phagocytes performed a variety of other basic biological jobs
that molded and
maintained the healthy function of normal tissues for the animal.
But immunology was a highly
contentious field in those days, and Metchnikoff, who was considered fiery and
difficult, wasn’t taken seriously at first by his peers. Many of them believed
instead that antibodies and other substances in the blood plasma, not cells,
were the primary agents of immunity. It was years before subsequent research
substantiated Metchnikoff’s cellular immunology concepts and he was recognized
for his work on the macrophage, which quickly became one of the immune system’s
star players. (In 1908 he and Paul Ehrlich shared a Nobel Prize for their
separate studies of the basis of immunity.)
The next century brought some of
the greatest advances in medicine and immunology, and amid the exuberant
fanfare for these discoveries, the nonimmunological roles that Metchnikoff had
suggested for the macrophage faded into the background. But now, because of
advances in immunology and single-cell
RNA sequencing, these roles are coming back into focus.
The Heart of the Matter
Metchnikoff would probably have
found Molkentin’s heart study validating. The cells that delivered the healing
boost to the hearts of the mice are a subset of what are called tissue-resident
macrophages.
Unlike the macrophages that
circulate in the blood and look for pathogens, these cells migrate into the
heart during embryonic development and remain there for the rest of their
lives. Over the past decade or so, evidence has accumulated that they perform a
variety of tasks, such as aiding in the maturation
of coronary vasculature and maintaining a proper heartbeat.
“They’re doing activities that
are not normally associated with immunology, such as helping tissues reshape
and change in response to stresses, or repair and regenerate, or even conduct
electricity,” said Kory Lavine, an assistant professor of medicine at the
Washington University School of Medicine in St. Louis.
Lavine gained some of the first
insights into the origins of tissue-resident
macrophages in the heart while studying sex-mismatched heart
transplants — cases in which the heart of a female donor went to a male
recipient or vice versa. In biopsied tissues, he was able to see that the
macrophages in the heart were from the original donor, which meant that they
stayed in the heart for the lifetime of the organ.
Lucy Reading-Ikkanda/Quanta
Magazine
In 2014, Lavine published a paper
showing that when an embryonic heart is damaged, these cells can repair and
regenerate the tissue. Then in 2016, his group presented evidence that
CCR macrophages in the heart actively sculpt the mature layout of the organ’s
blood vessels. During embryonic development, blood vessels are laid down in the
heart before the blood begins circulating. Once blood flow starts, however,
vessels are weeded out so that only the best routes are maintained. Lavine
found that CCR macrophages are integral to this process.
A few years ago, research was
published showing that macrophages are abundant throughout an electrically
conductive region of the heart known as the atrioventricular (AV) node, which
connects the heart chambers called the atria and ventricles in mice and humans.
The macrophages in the AV are elongated, with projections that extend their
reach. When scientists bred mice that lacked these cells, they found
significant delays in the conduction of electrical signals through the AV node.
When they chemically blocked the activity of these macrophages, they witnessed
“AV block,” an impairment of the electrical signal traveling from the atria to
the ventricles.
How the macrophages aid
conduction is still unclear, but it appears that their presence primes the
heart cells’ firing signals to travel more quickly. The finding has scientists
now looking into whether abnormalities in heart macrophages can lead to
arrhythmias in humans.
The heart is not unique. In fact,
most tissues and organs in the body have their own cache of tissue-resident
macrophages. They have been found to carry out key functions, as if they were a
part of the organ in which they reside. In the brain, for example, they remove
axons and aid in the pruning of synapses during development. Those in adipose
tissue help to regulate body heat. Macrophages have even been found to aid
in the recycling
of iron in the spleen and liver.
From Killers to Builders
If macrophages are the greatest
multitaskers in the immune system, then natural killer cells are the most
poorly named. NK cells were first identified for their ability to destroy tumor
cells on contact by blasting them with chemicals that induce apoptosis or
cellular suicide. They are powerful players in the immune system’s defensive
arsenal.
But almost from the time of their
discovery, scientists have noted that subpopulations of these NK cells reside
full time in the liver, skin, kidney and uterus. And unlike their deadly
cousins, these cells don’t kill.
Two natural
killer (NK) cells (yellow) attack a cancer cell (red) in this artificially
colored micrograph. NK cells took their name from how avidly they attacked
abnormal and infected cells, but some of them also help to ensure the blood
supply to the uterus during pregnancy.
Eye of Science/Science Source
In the uterus, NK cells make up
70% of the white blood cells during the first half of pregnancy. Early
experiments in mice showed that when these uterine NK cells were isolated and
pitted against mouse lymphoma cells — a natural adversary — they lacked the
cancer-fighting powers of their immune system brethren. This revelation
prompted scientists to ask what, exactly, the NK cells were doing there.
Early work by the pioneering
scientist Anne Croy of Queen’s University pointed to an answer.
The Canadian scientist, who was trained as a veterinarian, studied pregnancy
and the immune system in mice. She noticed that these cells tended to
congregate at the very edge of the maternal-fetal interface in pregnant mice,
where the placenta meets up with the lining of the uterus. That fact led her to
hypothesize that NK cells were involved in the remodeling of blood vessels in
the uterus.
Any good immunologist will tell
you, you need an inflammatory response to get healing.
Jeffery Molkentin, Cincinnati
Children’s Hospital
During pregnancy, fetal cells
“remodel” maternal arteries in the uterus so that they will no longer respond
to the mother’s fight-or-flight signals. Imagine a pregnant mouse being chased
by a cat (or a pregnant woman fleeing a tiger): The rush of adrenaline she
experiences makes the blood vessels to her organs shrink and shunts blood to
her muscles to aid her escape. But those changes could be detrimental and
possibly lethal for a fetus in her uterus by depriving it of blood and the
oxygen and nutrients it delivers. Evolution has invented this remodeling
mechanism as protection against that physiological response to a crisis.
In a set of landmark experiments,
Croy showed that uterine NK cells control the vascular changes that happen
during pregnancy by means of substances they secrete from their granules. In NK
cells that circulate throughout the body, similar granules are normally filled
with an assassin’s cocktail of toxins, but in the uterine NK cells, they carry
growth factors and chemokines (messenger molecules) that attract other cells.
Once released, these molecules attract endothelial cells and trophoblasts,
which are fetal cells from the placenta that can also remodel the blood vessels
in the uterus.
“Instead of being killers, they
are really builders,” Francesco Colucci, an immunologist at the University of
Cambridge, said of the NK cells. Colucci published research showing that
uterine NK cells regulate the extent to which fetal cells can invade
the uterus, and he is now using RNA sequencing techniques to characterize
different types of uterine NK cells (as described in a paper he published on
this in Nature Communications in
late January).
“Natural killer cells are
actually playing a role in supporting healthy pregnancies, but it has got
nothing to do with killing,” said Haniffa. In 2018, Haniffa and colleagues
published a map of the maternal-fetal interface with single-cell resolution
that revealed the gene activity of these NK cells, further elucidating their
dexterity.
Mapping Out a Theory
Natural killers and macrophages
are some of the best-characterized examples of multitasking immune cells, but
there are many more. Regulatory T cells, or Tregs, a subset of the T
lymphocytes, modulate the immune response. But they have been shown to
be involved in other processes as diverse as hair growth in
the skin and insulin regulation in fat tissue. Innate
lymphoid cells — lymphocytes that do not express the same antigen
receptors as B and T cells — are involved in metabolism and even the healthy
function of the nervous system. Also, combinations of these cells have been
observed in crosstalk with stem cells, helping to maintain the regeneration
of tissues that constantly turn over like the skin and the intestinal
lining.
When the names were given to
immune cells, it was always in the context of what they did to protect us.
Muzlifah Haniffa, Newcastle
University
“For a long time, people thought
of the immune system as basically what’s in your blood,” Haniffa said. “Then
they realized that your immune system doesn’t just exist in your blood, it exists
in every tissue.” Moreover, the immune system cells embedded in tissues and
even among your microbiota are in communication. The cells in the brain called
microglia have traditionally not been recognized as part of the immune system,
but they
consume cellular debris like macrophages. They have also been shown
to respond
to signals from gut microbiota. “We should view the immune system as a
bit like a matrix that exists in the entire body,” Haniffa said.
Aviv
Regev, a computational biologist at the Broad Institute who helped launch
the Human Cell Atlas, echoes these thoughts. You can think of immune cells as
one of the major sensing systems in the body along with the nervous system, she
said: “We often thought of [immune cells] in narrower functional terms, but we
increasingly realize that their roles are broader.”
Haniffa wants to explore the
immune system’s role in embryonic development. Last October, she and her
colleagues published a study in Nature that detailed the gene activity
in individual cells from the developing blood system and immune system of a
human embryo. They profiled more than 200,000 cells from the embryonic yolk
sac, liver, skin and kidneys at various points between the seventh and 17th
weeks of development. The work was a milestone because it was the first effort
to map the development of the human immune and blood systems, including red and
white blood cells, with single-cell resolution.
According to Shruti Naik,
a stem cell biologist and single-cell researcher at New York University, “this
paper has huge implications” for our “understanding of not just human gestation
but inborn errors in immunity and developmental disorders.”
Haniffa found that a trove of
immune cells was present very early in human development, which she thinks
could signify that the cells have an important part to play in the development
of tissues. She points out that mast cells, which are traditionally involved in
allergic reactions, show up in the yolk sac during the first trimester. Why
would they be there when allergy is not typically an issue for embryos? But
mast cells have been also implicated in blood vessel development in cancer, so
Haniffa wonders whether they might have something to do with healthy blood
vessel formation too.
Regev notes that more research is
still needed to elucidate the functions of mast cells at various stages of
development. But to her, “the possibility that the cells that arise early have
more diverse functions in developing tissue is a very compelling hypothesis.”
Posts
