Understanding Itch: New Insights at the Intersection of the Nervous System and Immune System

Through a series of preclinical experiments, collaborators pinpointed a key molecular player that could represent a new therapeutic target for intractable chronic itch

Eczema, or atopic dermatitis (AD), is sometimes called “the itch that rashes.” Often, the itch begins before the rash appears, and, in many cases, the itchiness of the skin condition never really goes away. Approximately 9.6 million children and 16.5 million adults in the U.S. have AD, which can have a serious effect on quality of life for patients. Although much has been learned about the uncomfortable sensation that triggers the desire to scratch, many mysteries remain about chronic itch, making it a challenge to treat. A paper by authors from Brigham and Women’s Hospital and Harvard Medical School published in The Proceedings of the National Academy of Sciences, offers new clues about the underlying mechanisms of itch. Findings suggest a key molecular player known as cysteine leukotriene receptor 2 (CysLT2R) that may be a new target for intractable chronic itch.

“In atopic dermatitis, the itching can be horrific and it can aggravate disease,” said co-corresponding author K. Frank Austen, MD, a senior physician in the Division of Allergy and Clinical Immunology at the Brigham. Austen is also the AstraZeneca Professor of Respiratory and Inflammatory Diseases, Emeritus, at Harvard Medical School. “We began collaborating for two reasons: one is an interest in science — I wandered into the study of what is now the cysteine leukotriene pathway decades ago, and I’ve been pursuing it ever since. The second reason is itch — understanding its cause and connections to neurons.”

Austen and his lab, which focuses on the molecular components that contribute to allergic inflammation, collaborated with Isaac Chiu, PhD, an assistant professor of Immunology at Harvard Medical School. The team also included researchers at the Center for Immunology & Inflammatory Diseases at Massachusetts General Hospital and at the University of Texas at Dallas.

“As a neuro-immunologist, I’m interested in how the nervous system and immune system cross-talk,” said Chiu, co-corresponding author of the study. “Itch arises from a subset of neurons, and acute itch may be a protective response to help us remove something that’s irritating the skin. However, chronic itch is not protective and can be pathological. The underlying mechanism that activates neurons and causes chronic itch is not well understood and new treatment is needed.”

Chiu, Austen and colleagues set out to elucidate the molecular mechanisms that may trigger chronic itch. To do so, they looked for gene activity in dorsal root ganglia (DRG) neurons linked to itch in mice. They found a striking level of CysLT2R, which was uniquely and highly expressed in these specific neurons. They also found expression of this receptor in human DRG neurons. This led the researchers to focus their analysis on the receptor’s role in itch signaling. Additional studies showed that activating this receptor induced itching in a mouse model of AD, but not in other mouse models. Mice that lacked CysLT2R showed decrease itching. Collectively, their findings pointed to the receptor’s key role in causing itch and potentially contributing to AD.

Lead author Tiphaine Voisin, PhD, carried out many of the preclinical experiments in mouse models of AD during her time in the Chiu lab at HMS.

“The last ten years or so of research in the field of chronic itch have shown the importance and the complexity of the interactions between the immune system and the nervous system,” said Voisin. “It was very exciting to explore the contribution of cysteine leukotrienes in these neuro-immune cross-talks leading to itch, including in a mouse model of AD.”

Leukotrienes are a class of lipid molecules that originate from white blood cells, such as mast cells, which are involved in allergy and inflammation. Today, the leukotriene inhibitor montelukast, which targets CysLT1R, is used to treat asthma but does not provide relief from itch. No clinically approved inhibitors of CysLT2R currently exist and, while the researchers have seen evidence of the receptors in humans, until an inhibitor is developed and trialed in humans, it will remain an open question as to whether the new target can lead to a therapy for patients.

While Chiu and Austen are eager to see their findings prompt treatment improvements, Austen, who has been pursuing leukotrienes since the 1970s, also notes the importance of making new discoveries and unexpected connections through research.

“I do believe that science is bottom up, not top down,” said Austen. “The joy of research is doing it for the pleasure of finding out something you didn’t know. The immune system is far more complex than we give it credit for. Understanding the involvement of nerves is an immense step forward — it’s been a missing piece in the study of inflammation. In my view, this is immensely important to connect neuroscience with those of us committed to studying inflammation.”

Funding for this work was provided by the National Institutes of Health (DP2AT009499, R01AI130019 and NS111929), the Food Allergy Science Initiative, the Burroughs Wellcome Fund, the Brigham and Women’s Hospital Hypersensitivity Fund, the National Institutes of Allergy and Infectious Diseases (K08 AI132723), and the American Academy of Allergy, Asthma & Immunology Foundation Faculty Development Award.

Paper cited: Voisin, T et al. “The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch” PNAS DOI: 10.1073/pnas.2022087118

Total Knee Replacement a Cost-Effective Treatment Option for Patients with Severe Knee Osteoarthritis and Extreme Obesity

Despite possible complications, procedure leads to substantial increases in quality-adjusted life expectancy for these patients as well as good value for resources spent.

Knee osteoarthritis is a painful condition that affects over 14 million U.S. adults, many of whom have extreme obesity, defined by body mass index (BMI) greater than 40kg/m2. Total knee replacement (TKR) is often recommended to treat advanced knee osteoarthritis, but surgeons may be hesitant to operate on patients with extreme obesity due to concerns about the increased risks of tissue infection, poor wound healing and higher risk of implant failure. Using an established, validated and widely published computer simulation called the Osteoarthritis Policy (OAPol) Model, researchers from Brigham and Women’s Hospital, together with collaborators from Yale and Boston University Schools of Medicine, quantified the tradeoff between the benefits and adverse events, taking into consideration costs of forgoing versus pursuing TKR. They found that across older and younger age groups, TKR is a cost-effective treatment for these patients. Findings are published in Annals of Internal Medicine.

“People with extreme obesity experience substantial pain reduction from TKR, leading to meaningful improvements in quality-adjusted life expectancy. High BMI should not serve as a barrier for people seeking this procedure,” said corresponding author Elena Losina, PhD, a founding director of the Policy and Innovation eValuation in Orthopedic Treatments Center and a co-director of the Brigham’s Orthopedic and Arthritis Center for Outcomes Research. “From a health policy perspective, this operation offers a very good value for the dollars spent.”

The computer model used by the researchers, OAPol, combines clinical and economic data from national datasets to forecast the clinical course of patients who decide to receive or forgo TKR. In the model, each treatment choice is associated with benefits (improvements in pain leading to better quality of life), drawbacks (surgery complications, continuous pain reducing quality of life) and costs. The model tallies the data from a large number of patients to calculate an incremental cost-effectiveness ratio of TKR, calculated as dollars for quality adjusted life year (QALY) gained. The researchers reported favorable cost-effectiveness ratios of $35,200 and $54,100 per QALY for patients younger and older than 65 years, respectively. The researchers noted that most patients with extreme obesity and advanced knee osteoarthritis considering TKR are in the younger age range. These data, they suggest, may help to diminish concerns regarding the value of TKR in these patients.

“Instead of questioning whether or not to do surgery for people with extreme obesity, the conversation should be about how to accommodate these patients and provide accurate information about what to expect post-surgery,” Losina said. “Ultimately, this study raises the question of how to do the operation in a way that addresses all of the challenges that may arise. This is a discussion that should take place between individual patients and physicians, discussing all the risks, complications, and benefits as well as considerations of operating room accommodations that would optimize the work of orthopedic surgeons performing TKR in these patients.”

This project was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grants R01 AR074290, K24 AR057827, K24 AR070892, P30 AR072571, and P30 AR072577.

Paper cited: Chen AT et al., “The value of total knee replacement (TKR) in knee osteoarthritis patients with BMI≥40kg/m2: A cost-effectiveness analysis” Annals of Internal Medicine DOI: 10.7326/M20-4722

SARS-CoV-2 Hijacks Two Key Metabolic Pathways to Rapidly Replicate in Host Cells

Blocking folate metabolism with oral, prophylactic drugs could reduce viral replication in infected cells

When SARS-CoV-2, the virus that causes COVID-19, infects a human cell, it quickly begins to replicate by seizing the cell’s existing metabolic machinery. The infected cells churn out thousands of viral genomes and proteins while halting the production of their own resources. Researchers from Brigham and Women’s Hospital, Massachusetts General Hospital (MGH), and the Broad Institute, studying cultured cells shortly after infecting them with the virus, now have more insight into the metabolic pathways co-opted by the virus. The findings, published in Nature Communications, highlight the potential therapeutic benefit of drugs such as methotrexate, which inhibit folate and one-carbon metabolic pathways appropriated by the virus.

“One of the things we’re lacking in this pandemic is a pill that can be taken orally, as a prophylactic agent, before someone is hospitalized or even before they’re infected,” said corresponding author Benjamin Gewurz, MD, PhD, of the Division of Infectious Diseases at the Brigham. “Monoclonal antibodies have a lot of promise but need to be given intravenously. Blocking the metabolism pathways that viruses rely on to replicate could be a new strategy for treating patients at an early timepoint.”

To identify which metabolic pathways to target, the researchers obtained samples of the virus and cultivated them in a highly protected facility called a BSL-3 laboratory, located at the Broad Institute. They then paired up with the laboratory of co-senior author Vamsi Mootha, MD, of MGH, to apply mass spectrometry approaches to identify the resources being consumed and produced by healthy cells and infected cells. They studied the infected cells at an “eclipse point,” eight hours after infection, when the virus has begun manufacturing its RNA and proteins but has not yet exerted a serious effect on host cell growth and survival.

In analyzing the amino acids and thousands of chemical metabolites produced by the cells, the researchers observed that infected cells had depleted stores of glucose and folate. They demonstrated that the SARS-CoV-2 virus diverts building blocks from glucose production to the assembly of purine bases, which are necessary for creating large amounts of viral RNA. Additionally, they found that the 1-carbon pathway used to metabolize folate was hyperactive, thus supplying the virus with more carbon groups for making bases for DNA and RNA.

Drugs that inhibit folate metabolism, like methotrexate, are often used to treat autoimmune conditions like arthritis and could be therapeutic candidates for COVID-19. Methotrexate is currently being assessed as a treatment for the inflammation that accompanies more advanced COVID-19 infections, but the researchers suggest that it could also be beneficial early on. Their study also found that it could offer a synergistic effect when administered with the anti-viral drug remdesivir. Methotrexate’s immune-suppressing properties could make its proper administration as a prophylactic challenging, however. Researchers would need to determine how to maximize the drug’s antiviral effects without significantly compromising a patient’s natural immune response.

Still, Gewurz points out that oral antivirals are an important addition to an arsenal of therapies for COVID-19, serving both as an immediate treatment for infection as well as a defense against new variants and other coronaviruses.

“We’re hoping that, ultimately, we can find a way of preventing viruses from using cells’ metabolism pathways to replicate themselves because that could limit the ability of viruses to evolve resistance,” Gewurz said. “We’re starting to see new viral variants, and we’re hoping that we can stay ahead of that — treating patients before the virus has the chance to make copies of itself that could become resistant to antibodies.”

This work was supported by the National Institutes of Health (R01 AI137337, R01 CA228700, R35 GM122455), EMBO (ALTF 486-2018), a Burroughs Wellcome Career Award in Medical Sciences, the Howard Hughes Medical Institute and MassCPR. Gewurz and Mootha are listed as inventors on a patent application filed by the Broad Institute based on results from this manuscript.

Paper cited: Zhang Y et al., “SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication” Nature Communications DOI: 10.1038/s41467-021-21903-z