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Tag Archives: protective
Harvard Medical Researchers Discover Surprising Protective Properties of Pain
Harvard Medical School researchers have analyzed the molecular crosstalk between pain fibers in the gut and goblet cells that line the walls of the intestine. The work shows that chemical signals from pain neurons induce goblet cells to release protective mucus that coats the gut and shields it from damage. The findings show that intestinal pain is not a mere detection-and-signaling system, but plays a direct protective role in the gut. Credit: Chiu Lab/Harvard Medical School
What if pain is more than just a mere alarm bell?
New research in mice illuminates how pain neurons shield the gut from damage.
Pain is one of evolution’s most effective mechanisms for detecting injury and letting us know that something is wrong. It acts as a warning system, telling us to stop and pay attention to our body.
But what if pain is more than just a mere alarm signal? What if pain is in itself a form of protection?
A new study led by researchers at Harvard Medical School suggests that may well be the case in mice.
The surprising research reveals that pain neurons in the mouse gut regulate the presence of protective mucus under normal conditions and stimulate intestinal cells to release more mucus during states of inflammation. The study was published on October 14 in the journal Cell.
The work describes the steps of a complex signaling cascade, demonstrating that pain neurons engage in direct crosstalk with mucus-containing gut cells, known as goblet cells.
Goblet cells arise from pluripotent stem cells and get their name from their cup-like appearance that resembles a goblet. Their main function is to secrete mucin and create a protective mucus layer. Goblet cells are also believed to have a role in the regulation of the immune system.
“It turns out that pain may protect us in more direct ways than its classic job to detect potential harm and dispatch signals to the brain. Our work shows how pain-mediating nerves in the gut talk to nearby epithelial cells that line the intestines,” said study senior investigator Isaac Chiu. “This means that the nervous system has a major role in the gut beyond just giving us an unpleasant sensation and that it’s a key player in gut barrier maintenance and a protective mechanism during inflammation.” Chiu is an associate professor of immunobiology in the Blavatnik Institute at HMS.
A direct conversation
Our intestines and airways are studded with goblet cells. Named for their cup-like appearance, goblet cells contain gel-like mucus made of proteins and sugars that acts as protective coating that shields the surface of organs from abrasion and damage. The new research found that intestinal goblet cells release protective mucus when triggered by direct interaction with pain-sensing neurons in the gut.
In a set of experiments, the researchers observed that mice lacking pain neurons produced less protective mucus and experienced changes in their intestinal microbial composition — an imbalance in beneficial and harmful microbes known as dysbiosis.
To clarify just how this protective crosstalk occurs, the scientists analyzed the behavior of goblet cells in the presence and in the absence of pain neurons.
They found that the surfaces of goblet cells contain a type of receptor, called RAMP1, that ensures the cells can respond to adjacent pain neurons, which are activated by dietary and microbial signals, as well as mechanical pressure, chemical irritation or drastic changes in temperature.
The experiments further showed that these receptors connect with a chemical called CGRP, released by nearby pain neurons, when the neurons are stimulated. These RAMP1 receptors, the researchers found, are also present in both human and mouse goblet cells, thus rendering them responsive to pain signals.
Experiments further showed that the presence of certain gut microbes activated the release of CGRP to maintain gut homeostasis.
“This finding tells us that these nerves are triggered not only by acute inflammation, but also at baseline,” Chiu said. “Just having regular gut microbes around appears to tickle the nerves and causes the goblet cells to release mucus.”
This feedback loop, Chiu said, ensures that microbes signal to neurons, neurons regulate the mucus, and the mucus keeps gut microbes healthy.
In addition to microbial presence, dietary factors also played a role in activating pain receptors, the study showed. When researchers gave mice capsaicin, the main ingredient in chili peppers known for its ability to trigger intense, acute pain, the mice’s pain neurons got swiftly activated, causing goblet cells to release abundant amounts of protective mucus.
By contrast, mice lacking either pain neurons or goblet cell receptors for CGRP were more susceptible to colitis, a form of gut inflammation. The finding could explain why people with gut dysbiosis may be more prone to colitis.
When researchers gave pain-signaling CGRP to animals lacking pain neurons, the mice experienced rapid improvement in mucus production. The treatment protected mice against colitis even in the absence of pain neurons.
The finding demonstrates that CGRP is a key instigator of the signaling cascade that leads to the secretion of protective mucus.
“Pain is a common symptom of chronic inflammatory conditions of the gut, such as colitis, but our study shows that acute pain plays a direct protective role as well,” said study first author Daping Yang, a postdoctoral researcher in the Chiu Lab.
A possible downside to suppressing pain
The team’s experiments showed that mice lacking pain receptors also had worse damage from colitis when it occurred.
Given that pain medications are often used to treat patients with colitis, it may be important to consider the possible detrimental consequences of blocking pain, the researchers said.
“In people with inflammation of the gut, one of the major symptoms is pain, so you might think that we’d want to treat and block the pain to alleviate suffering,” Chiu said. “But some part of this pain signal could be directly protective as a neural reflex, which raises important questions about how to carefully manage pain in a way that does not lead to other harms.”
Additionally, a class of common migraine medications that suppress the secretion of CGRP may damage gut barrier tissues by interfering with this protective pain signaling, the researchers said.
“Given that CGRP is a mediator of goblet cell function and mucus production, if we are chronically blocking this protective mechanism in people with migraine and if they are taking these medications long-term, what happens?” Chiu said. “Are the drugs going to interfere with the mucosal lining and people’s microbiomes?”
Goblet cells have multiple other functions in the gut. They provide a passage for antigens — proteins found on viruses and bacteria that initiate a protective immune response by the body — and they produce antimicrobial chemicals that protect the gut from pathogens.
“One question that arises from our current work is whether pain fibers also regulate these other functions of goblet cells,” Yang said.
Another line of inquiry, Yang added, would be to explore disruptions in the CGRP signaling pathway and determine whether malfunctions are at play in patients with genetic predisposition to inflammatory bowel disease.
Reference: “Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection” by Daping Yang, Amanda Jacobson, Kimberly A. Meerschaert, Joseph Joy Sifakis, Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel A. Rucker, Deepika Sharma, Alexandra Sontheimer-Phelps, Glendon S. Wu, Liwen Deng, Michael D. Anderson, Samantha Choi, Dylan Neel, Nicole Lee, Dennis L. Kasper, Bana Jabri, Jun R. Huh, Malin Johansson, Jay R. Thiagarajah, Samantha J. Riesenfeld and Isaac M. Chiu, 14 October 2022, Cell.
DOI: 10.1016/j.cell.2022.09.024
Co-authors included Amanda Jacobson, Kimberly Meerschaert, Joseph Sifakis, Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel Rucker, Deepika Sharma, Alexandra Sontheimer-Phelps, Glendon Wu, Liwen Deng, Michael Anderson, Samantha Choi, Dylan Neel, Nicole Lee, Dennis Kasper, Bana Jabri, Jun Huh, Malin Johansson, Jay Thiagarajah, and Samantha Riesenfeld.
The work was supported by the National Institutes of Health (grants R01DK127257, R35GM142683, P30DK034854, and T32DK007447); the Food Allergy Science Initiative; the Kenneth Rainin Foundation; and the Digestive Diseases Research Core Center under grant P30 DK42086 at the
Hubble Space Telescope Detects Protective Shield Defending a Pair of Dwarf Galaxies
Scientists have used spectroscopic observations of ultraviolet light from quasars to detect and map the Magellanic Corona, a diffuse halo of hot, supercharged gas surrounding the Small and Large Magellanic Clouds. Shown in purple, the corona stretches more than 100,000 light-years from the main mass of stars, gas, and dust that make up the Magellanic Clouds, intermingling with the hotter and more extensive corona that surrounds the Milky Way. Credit: NASA, ESA, Leah Hustak (STScI)
Researchers confirm the existence of the elusive Magellanic Corona, a protective halo of hot, ionized gas previously known only in theory.
For billions of years, the
Using a combination of the unique ultraviolet vision of the 
Nearly 200,000 light-years from Earth, the Large Magellanic Cloud, a satellite galaxy of the Milky Way, floats in space, in a long and slow dance around our galaxy. As the Milky Way’s gravity gently tugs on its neighbor’s gas clouds, they collapse to form new stars. In turn, these light up the gas clouds in a kaleidoscope of colors, visible in this image from the NASA/ESA Hubble Space Telescope. Credit: NASA, ESA, Acknowledgment: Josh Lake
For billions of years, the Large and Small Magellanic Clouds – the Milky Way’s largest satellite galaxies – have followed a perilous journey. Orbiting one another as they are pulled in toward our home galaxy, they have begun to unravel, leaving behind trails of gaseous debris. And yet these dwarf galaxies remain intact, with ongoing vigorous star formation, leaving astronomers baffled.
“A lot of people were struggling to explain how these streams of material could be there,” said Dhanesh Krishnarao, assistant professor at Colorado College. “If this gas was removed from these galaxies, how are they still forming stars?”
A team of astronomers led by Krishnarao has finally found the answer, with the help of data from
However, while covering a huge portion of the southern sky and extending more than 100,000 light-years from the Magellanic clouds, the corona is effectively invisible. In fact, mapping it required scouring through 30 years of archived data for suitable measurements.
Scientists think that a galaxy’s corona is a remnant of the primordial cloud of gas that collapsed to form the galaxy billions of years ago. Although coronas have been seen around more distant dwarf galaxies, astronomers had never before been able to probe one in as great of detail as this.
“There’re lots of predictions from computer simulations about what they should look like, how they should interact over billions of years, but observationally we can’t really test most of them because dwarf galaxies are typically just too hard to detect,” said Krishnarao. Because they are right on our doorstep, the Magellanic Clouds provide a fantastic opportunity to study how dwarf galaxies interact and evolve.
In search of direct evidence of the Magellanic Corona, the research team sifted through the Hubble and FUSE archives for ultraviolet observations of quasars located billions of light-years behind it. Quasars are the extremely bright cores of galaxies containing massive active black holes. Although the scientists reasoned that although the corona would be too dim to see on its own, they thought that it should be visible as a sort of fog obscuring and absorbing distinct patterns of bright light from quasars in the background. Hubble observations of quasars were used in the past to map the corona surrounding the Andromeda galaxy.
By analyzing patterns in ultraviolet light from 28 quasars, the researchers were able to detect and characterize the material surrounding the Large Magellanic Cloud and confirm that the corona exists. As predicted, the quasar spectra are imprinted with the distinct signatures of carbon, oxygen, and silicon that make up the halo of hot
“Anything that tries to pass into the galaxy has to pass through this material first, so it can absorb some of that impact,” explained Krishnarao. “In addition, the corona is the first material that can be extracted. While giving up a little bit of the corona, you’re protecting the gas that’s inside the galaxy itself and able to form new stars.”
Reference: “Observations of a Magellanic Corona” by Dhanesh Krishnarao, Andrew J. Fox, Elena D’Onghia, Bart P. Wakker, Frances H. Cashman, J. Christopher Howk, Scott Lucchini, David M. French and Nicolas Lehner, 28 September 2022, Nature.
DOI: 10.1038/s41586-022-05090-5
The Hubble Space Telescope is a project of international cooperation between NASA and ESA (European Space Agency). NASA’s Goddard Space Flight Center in Greenbelt, Maryland, manages the telescope. The Space Telescope Science Institute (STScI) in Baltimore, Maryland, conducts Hubble science operations. STScI is operated for NASA by the Association of Universities for Research in Astronomy in Washington, D.C.
The Far Ultraviolet Spectroscopic Explorer (FUSE) was a project of international cooperation between NASA, CSA (Canadian Space Agency), and CNES (French Space Agency), and was in operation between 1999 and 2007.
Hubble Space Telescope Detects Protective Shield Defending a Pair of Dwarf Galaxies
Scientists have used spectroscopic observations of ultraviolet light from quasars to detect and map the Magellanic Corona, a diffuse halo of hot, supercharged gas surrounding the Small and Large Magellanic Clouds. Shown in purple, the corona stretches more than 100,000 light-years from the main mass of stars, gas, and dust that make up the Magellanic Clouds, intermingling with the hotter and more extensive corona that surrounds the Milky Way. Credit: NASA, ESA, Leah Hustak (STScI)
Researchers confirm the existence of the elusive Magellanic Corona, a protective halo of hot, ionized gas previously known only in theory.
For billions of years, the
Using a combination of the unique ultraviolet vision of the
Nearly 200,000 light-years from Earth, the Large Magellanic Cloud, a satellite galaxy of the Milky Way, floats in space, in a long and slow dance around our galaxy. As the Milky Way’s gravity gently tugs on its neighbor’s gas clouds, they collapse to form new stars. In turn, these light up the gas clouds in a kaleidoscope of colors, visible in this image from the NASA/ESA Hubble Space Telescope. Credit: NASA, ESA, Acknowledgment: Josh Lake
For billions of years, the Large and Small Magellanic Clouds – the Milky Way’s largest satellite galaxies – have followed a perilous journey. Orbiting one another as they are pulled in toward our home galaxy, they have begun to unravel, leaving behind trails of gaseous debris. And yet these dwarf galaxies remain intact, with ongoing vigorous star formation, leaving astronomers baffled.
“A lot of people were struggling to explain how these streams of material could be there,” said Dhanesh Krishnarao, assistant professor at Colorado College. “If this gas was removed from these galaxies, how are they still forming stars?”
A team of astronomers led by Krishnarao has finally found the answer, with the help of data from
However, while covering a huge portion of the southern sky and extending more than 100,000 light-years from the Magellanic clouds, the corona is effectively invisible. In fact, mapping it required scouring through 30 years of archived data for suitable measurements.
Scientists think that a galaxy’s corona is a remnant of the primordial cloud of gas that collapsed to form the galaxy billions of years ago. Although coronas have been seen around more distant dwarf galaxies, astronomers had never before been able to probe one in as great of detail as this.
“There’re lots of predictions from computer simulations about what they should look like, how they should interact over billions of years, but observationally we can’t really test most of them because dwarf galaxies are typically just too hard to detect,” said Krishnarao. Because they are right on our doorstep, the Magellanic Clouds provide a fantastic opportunity to study how dwarf galaxies interact and evolve.
In search of direct evidence of the Magellanic Corona, the research team sifted through the Hubble and FUSE archives for ultraviolet observations of quasars located billions of light-years behind it. Quasars are the extremely bright cores of galaxies containing massive active black holes. Although the scientists reasoned that although the corona would be too dim to see on its own, they thought that it should be visible as a sort of fog obscuring and absorbing distinct patterns of bright light from quasars in the background. Hubble observations of quasars were used in the past to map the corona surrounding the Andromeda galaxy.
By analyzing patterns in ultraviolet light from 28 quasars, the researchers were able to detect and characterize the material surrounding the Large Magellanic Cloud and confirm that the corona exists. As predicted, the quasar spectra are imprinted with the distinct signatures of carbon, oxygen, and silicon that make up the halo of hot
“Anything that tries to pass into the galaxy has to pass through this material first, so it can absorb some of that impact,” explained Krishnarao. “In addition, the corona is the first material that can be extracted. While giving up a little bit of the corona, you’re protecting the gas that’s inside the galaxy itself and able to form new stars.”
Reference: “Observations of a Magellanic Corona” by Dhanesh Krishnarao, Andrew J. Fox, Elena D’Onghia, Bart P. Wakker, Frances H. Cashman, J. Christopher Howk, Scott Lucchini, David M. French and Nicolas Lehner, 28 September 2022, Nature.
DOI: 10.1038/s41586-022-05090-5
The Hubble Space Telescope is a project of international cooperation between NASA and ESA (European Space Agency). NASA’s Goddard Space Flight Center in Greenbelt, Maryland, manages the telescope. The Space Telescope Science Institute (STScI) in Baltimore, Maryland, conducts Hubble science operations. STScI is operated for NASA by the Association of Universities for Research in Astronomy in Washington, D.C.
The Far Ultraviolet Spectroscopic Explorer (FUSE) was a project of international cooperation between NASA, CSA (Canadian Space Agency), and CNES (French Space Agency), and was in operation between 1999 and 2007.
