In a study aimed at investigating the mechanisms that exacerbate rheumatoid arthritis in smokers, researchers at the Center for Inflammatory Diseases Research (CRID), which is linked to the University of Sao Paulo (USP) in Brazil, found a new pathway for the inflammatory process. Found related to bone damage caused by rheumatoid arthritis. This discovery opens up new therapeutic intervention opportunities to mitigate the effects of the disease, for which there is currently no specific treatment.
Articles about research are published in Bulletin of the National Academy of Sciences (PNAS).. Researchers have identified the effects of molecular mechanisms involved in the inflammatory process. Release by T lymphocytes of extracellular vesicles loaded with genetic material (microRNA). Vesicles reach cells in bone tissue and increase the formation of osteoclasts, cells that destroy the bone matrix of joints (an important function in bone maintenance, repair, and remodeling).
This study aims to better understand how cigarette smoke exacerbates the inflammatory process in rheumatoid arthritis. We have discovered a pathway associated with bone damage. This is an important finding, as pain and inflammation are treated with drugs, but bone damage, a debilitating complication of the disease, is virtually irreversible. “
Fernando de Queiroz Cunha, Senior Researcher at CRD, one of the FAPESP-supported Research, Innovation and Dissemination Centers (RIDCs)
Rheumatoid arthritis is an autoimmune disease, and for unknown reasons, the immune system mistakenly attacks a pathogen that invades a part of the patient’s body. Inflammation caused by an overreaction of the immune system is known to involve Th17 cells. T cells It creates subtypes and cascade effects such as the release of cytokines (signal transduction proteins), including IL-17, and other molecules involved in disease progression.
Smoking is known to be an aggravating factor in rheumatoid arthritis. Previous studies by the same CRID group have shown that cigarette smoke exacerbates the inflammatory process of arthritis, primarily by activating the aryl hydrocarbon receptor (AhR) in Th17 cells.
“AhR is an intracellular sensor that detects pollutants involved in the inflammatory process. When AhR is activated on T cells by a specific ligand, it further differentiates into Th17. The increase in Th17 cells exacerbates the inflammatory process. I don’t smoke, but it causes rheumatoid arthritis, which exacerbates the disease, “said Paula Donate, a CRCI researcher whose late doctoral studies were supported by FAPESP.
Donate explained that AhR functions primarily as a transcription factor. “When this receptor is activated by an external factor such as cigarette smoke, it enters the cell nucleus along with other proteins and promotes transcription of various genes, including microRNA, a small intracellular regulatory RNA. “She said.
In this study, researchers wanted to find out which microRNAs in Th17 cells were more expressed by AhR activation. Their analysis pointed to miR-132. They analyzed the full set of microRNAs expressed by Th17 cells and correlated the results with data from laboratory studies involving mouse and human patient samples.
“But surprisingly, when T cells were treated with a microRNA antagonist, the T cells continued to differentiate normally into Th17 cells, releasing cytokines characteristic of the inflammatory process in rheumatoid arthritis. If unaffected, it indicates that miR-132 may be released into extracellular media. “
When researchers isolated extracellular vesicles released by Th17 and studied them in vitro, a large amount of miR-132 packaged in extracellular vesicles acted as an inflammatory mediator and the enzyme cyclooxygenase 2 ( It was found that it induces osteoclast differentiation through inhibition of COX-2). ..
“Extracellular vesicles are an important cellular communication mechanism. They are released by virtually all cell types and are found in all types of body fluids. In the case of Th17 cells, the vesicles released in the joints produce microRNA. It transports to bone tissue and increases its volume. In short, this is a previously unknown mechanism that we have successfully elucidated and may be the basis for new treatments for joint injury in the future. There is. “