Inflammation

Posted on Rheumatoid arthritis

Unpicking the Origins of Rheumatoid Arthritis

New work on the precursors of inflammatory synovial macrophages
New work on the precursors of inflammatory synovial macrophages

Rheumatoid arthritis (RA) is an autoimmune disease that causes joint inflammation and destruction.1 There is currently no cure – and although there are many treatments, their effectiveness varies from person to person, suggesting an undefined pathogenic diversity.1 Deep characterisation of myeloid cell subsets by single-cell RNA sequencing across healthy and inflamed tissues in RA has identified new pathogenic cell states and subsets – with data from five large-scale studies. However, subset overlap across studies and compartments – such as in blood versus synovial tissue – has not yet been systematically investigated.

Presenting at the 2024 EULAR congress in Vienna, Sebastien Viatte explained, “We wanted to map monocyte subsets and states across studies and compartments to identify blood monocyte precursors of inflammatory synovial macrophage subsets observed in people with RA.”

With this in mind, the group set out to discover whether quiescent human blood monocyte states are pre-committed to an inflammatory synovial transcriptional program. First, peripheral blood mononuclear cells (PBMC) from healthy volunteers and RA patients with clinically well-controlled disease (quiescent PBMC) were enriched for monocytes by negative selection and subjected to single-cell RNA sequencing. The researcher then used published myeloid cell subsets to map onto their template based on the similarity of their expression scores. Hierarchical methods were applied to merge similar clusters and create a consensus map, and random forests were used to merge over-clustered data and identify novel myeloid cell states – and generate a final taxonomy of monocyte states in healthy human blood. Finally, to provide experimental validation at the protein level, PBMC from 19 RA patients with uncontrolled inflammation were deeply immunophenotyped, and inflammatory cell states with increased abundance in RA were identified.

All told, this work generated an exhaustive reference atlas comprising 11 monocyte states across anatomical compartments relevant to RA. For example, it was possible to show that different clusters, in fact, represent the same inflammatory synovial macrophage subset and are transcriptionally similar to an IL1B+ monocyte subset present in quiescent peripheral blood.

The findings also revealed that four quiescent monocyte states in the peripheral blood of both RA patients and healthy individuals expand in the blood of patients with uncontrolled RA. These likely represent blood precursors of pathogenic tissue macrophages.

This work is important because it not only defines a new monocyte cell taxonomy relevant for RA – with 11 continuous cell states that dynamically transition into each other across anatomical compartments – but also identifies potential blood precursors of pathogenic tissue macrophages.

Posted on Cancer, Cardiovascular disease, Diabetes, Obesity

Food’s Protective Power Against Inflammation

Inflammation can be good, signalling your body’s attempt to fight off infection or heal an injury. But when inflammatory cells soldier forth when you’re not sick or injured, chronic inflammation can ensue, contributing to obesity, cardiovascular disease, diabetes, and even autoimmune disease and cancer. The good—no, great—news is that the foods you eat can dramatically affect inflammation in your body, helping not only to prevent it but to fight it if it’s already started. Join Dr. Katsumoto as she discusses how foods can be anti-inflammatory—and how the ones you choose can also help the planet.

Posted on Lupus, Rheumatoid arthritis

RA and lupus – targets were discovered on RNA to short-circuit inflammation.

A new study details the high-throughput process for rapid screening and identification of mysterious long non-coding RNA.

New target for inflammation regulation discovered

UC Santa Cruz researchers have discovered that LOUP is a multifunctional gene in immune cells called monocytes. LOUP can work inside the nucleus to control its neighbour SPI1. They also discovered that LOUP RNA can leave the nucleus and produce a small peptide in the cytoplasm leading to an increase in the protein SPI1 and causing downregulation of NF-kB, the master controller of inflammation. CREDIT Carpenter Lab, UC Santa Cruz

UC Santa Cruz researchers have discovered a peptide in human RNA that regulates inflammation and may provide a new path for treating diseases such as arthritis and lupus. The team used a screening process based on the powerful gene-editing tool CRISPR to illuminate one of the biggest mysteries about our RNA–the molecule responsible for carrying out genetic information in our DNA.

This peptide originates within a long non-coding RNA (lncRNA) called LOUP. According to the researchers, the human genome encodes over 20,000 lncRNAs, making it the largest group of genes produced from the genome. But despite this abundance, scientists know little about why lncRNAs exist or what they do. This is why lncRNA is sometimes called the “dark matter of the genome.”

The study, published May 23 in the Proceedings of the National Academy of Sciences (PNAS), is one of the few in the existing literature to chip away at the mysteries of lncRNA. It also presents a new strategy for conducting high-throughput screening to rapidly identify functional lncRNAs in immune cells. The pooled-screen approach allows researchers to target thousands of genes in a single experiment, which is a much more efficient way to study uncharacterized portions of the genome than traditional experiments focusing on one gene at a time.

The research was led by immunologist Susan Carpenter, a professor and Sinsheimer Chair of UC Santa Cruz’s Molecular, Cell, and Developmental Biology Department. She studies the molecular mechanisms involved in protection against infection. Specifically, she focuses on the processes that lead to inflammation to determine lncRNAs’ role in these pathways.

“Inflammation is a central feature of just about every disease,” she said. “In this study, my lab focused on determining which lncRNA genes regulate inflammation.”

This meant studying lncRNAs in a type of white blood cell known as a monocyte. They used a modification of the CRISPR/Cas9 technology, called CRISPR inhibition (CRISPRi), to repress gene transcription and find out which of a monocyte’s lncRNA plays a role in whether it differentiates into a macrophage—another type of white blood cell that’s critical to a well-functioning immune response.

In addition, the researchers used CRISPRi to screen macrophage lncRNA for involvement in inflammation. Unexpectedly, they located a multifunctional region that can work as an RNA and contain an undiscovered peptide that regulates inflammation.

Ms Carpenter said that understanding that this specific peptide regulates inflammation gives drugmakers a target to block the molecular interaction behind that response to suppress it. “In an ideal world, you would design a small molecule to disrupt that specific interaction instead of targeting a protein that might be expressed throughout the body,” she explained. “We’re still far from targeting these pathways with that level of precision, but that’s definitely the goal. There’s a lot of interest in RNA therapeutics right now.”

Posted on Obesity

Fighting fat and inflammation: Scientists develop powerful new compounds.

Novel amino acid derivatives of menthol

The menthyl esters of valine (MV) and isoleucine (MI) are multi-faceted molecules with enhanced anti-inflammatory and anti-obesity activities. The discovery and development of such molecules can result in newer classes of therapeutic drugs to treat a wide range of metabolic disorders. CREDIT Gen-ichiro Arimura from Tokyo University of Science, Japan

Modified derivatives of natural products have led to significant therapeutic advances and commercial success in recent times. Menthol is a naturally occurring cyclic monoterpene alcohol found in various plants, particularly in members of the mint family such as peppermint and spearmint. It is a common ingredient found in a wide range of confectionaries, chewing gums and oral care products. Interestingly, menthol also has high medicinal value due to its analgesic, anti-inflammatory, and anti-cancer effects.

In a recent study, a team of researchers led by Professor Gen-ichiro Arimura from the Department of Biological Science and Technology, Tokyo University of Science, Japan, developed and investigated menthyl esters of valine (MV) and isoleucine (MI), which are derived from menthol by replacing its hydroxyl group with valine and isoleucine, respectively.

Their research findings were published in the Immunology journal on May 08, 2024. Sharing the motivation behind the present work, Prof. Arimura says, “The functional components of plants that contribute to human health have always intrigued me. Discovering new molecules from natural materials inspired our research team to develop these amino acid derivatives of menthol.”

The researchers began by synthesizing menthyl esters of six amino acids characterized by less-reactive side chains. Subsequently, they assessed the properties of these esters using in vitro cell line studies. Finally, they conducted experiments in mice to explore the effects of these compounds under induced disease conditions. The exceptional anti-inflammatory profiles of MV and MI was determined by assessing the transcript levels of tumor necrosis factor-α (Tnf) in stimulated macrophage cells. Remarkably, both MV and MI outperformed menthol in the anti-inflammatory assay. RNA sequencing analysis revealed that 18 genes involved in inflammatory and immune responses were effectively suppressed.

Elated with their findings, the researchers went a step further and investigated the mechanism of action of the menthyl esters. They discovered that liver X receptor (LXR) – an intracellular nuclear receptor, had an important role in the anti-inflammatory effects and this was independent of the cold-sensitive transient receptor TRPM8, which primarily detects menthol. Delving deeper into the LXR-dependant activation of MV and MI, they found that Scd1 gene – central to lipid metabolism was upregulated by LXR. Moreover, in mice with induced intestinal colitis, the anti-inflammatory effects were further validated with suppressed transcript levels of Tnf and Il6 genes by MV or MI, in an LXR-dependent manner.

Driven by the discovery of LXR-SCD1 intracellular machinery, Prof. Arimura and his team hypothesized the menthyl esters to possess anti-obesity properties. They found that these esters inhibited adipogenesis-fat accumulation, specifically at the mitotic clonal expansion stage in 3T3-L1 adipocyte cells. During animal studies, the diet-induced obesity in mice was ameliorated and adipogenesis was suppressed.

Menthyl esters possess unique advantages compared to other anti-inflammatory or anti-obesity compounds currently being researched or used. Their specific mechanisms of action, that contribute to their dual anti-inflammatory and anti-obesity effects sets them apart from other compounds and may make them particularly effective in addressing both inflammatory conditions and metabolic disorders. They could benefit specific populations like individuals with chronic inflammatory conditions, metabolic syndrome, or obesity-related complications.

 “Although this study focused on their functions and mechanisms of action in diseases modeled after inflammation and obesity, we expect that these compounds will also be effective against a wide range of lifestyle-related diseases caused by metabolic syndrome, such as diabetes and hypertension, as well as allergic symptoms,” says Prof. Arimura optimistically.

In conclusion, this study underscores the importance and value of multi-faceted molecules derived from naturally occurring substances. Future research involving these novel and superior menthyl esters may result in therapeutic compounds to tackle the ever-growing health concerns of obesity and inflammatory conditions.

Posted on Multiple Sclerosis

Managing Multiple Sclerosis Symptoms: Effective Ways to Reduce Inflammation

Managing MS symptoms with medication, diet, and lifestyle changes can help us live well with MS. In this video, I share information on how MS is an inflammatory disease and tips on how diet and lifestyle changes can help reduce inflammation. Reducing inflammation may help reduce symptoms and improve our quality of life. And who doesn’t want reduced symptoms and a better quality of life?!