Unveiling the Molecular Impact of Smoking on Lung Health. This illustration explores how smoke components in cigarette and e-cigarette smoke obscures critical chemicals that bind MR1 and disrupt T cell functions in the lungs. Image: Erica Tandori
Cigarette smoking is widespread and deadly, yet our understanding of how cigarette smoke actually causes serious respiratory illnesses in incomplete, which has severely hampered the development of effective treatments. In the Journal of Experimental Medicine (JEM) Australian researchers reveal how multiple chemicals found in cigarette smoke and e-cigarettes alter the function of a key type of immune cell found in the lungs.
The study suggests that these alterations make cigarette smokers, and those exposed to second- and third-hand smoke, more susceptible to respiratory infections, and exacerbate smoking-related inflammatory diseases such as chronic obstructive pulmonary disease (COPD).
Cigarette smoking is known to impair the immune system's response to infections and promote inflammation in the lungs that can lead to or exacerbate COPD, the third leading cause of death worldwide. COPD patients are more susceptible to influenza infections that can, in turn, exacerbate the underlying disease by increasing airway inflammation and promoting the destruction of the lung's air sacs. There are currently no effective treatments for COPD.
According to Dr Wael Awad, from Monash University's Biomedicine Discovery Institute, until now the mechanisms underlying the skewed immune responses in people exposed to cigarette smoke, and how they are related to smoke-associated diseases like COPD remain unclear," says Dr Awad, first author on the new JEM study.
Professor Jamie Rossjohn of Monash University's Biomedicine Discovery Institute co-led the study with Professor David P. Fairlie of the Institute for Molecular Bioscience at University of Queensland, Professor Alexandra J. Corbett of the University of Melbourne, based at the Peter Doherty Institute for Infection and Immunity, and Professor Philip M. Hansbro of the Centenary Institute and University of Technology Sydney.
In their study, the researchers looked at the effects of cigarette smoke on Mucosal-Associated Invariant T (MAIT) cells, a type of immune cell found in the lungs and other tissues of the body. MAIT cells help fight off bacterial and viral infections and can promote inflammation or tissue repair.
MAIT cells are activated by a protein called MR1 that is found in almost every cell of the body. MR1 recognizes chemicals produced by bacteria and presents them at the surface of infected cells in order to activate MAIT cells and initiate an immune response. "We suspected that some of the more than 20,000 chemicals present in cigarette smoke that smokers inhale might also bind to MR1 and influence the activity of MAIT cells in the lungs", Dr Awad said.
The researchers used computer modeling to predict which components of cigarette smoke might be recognized by MR1 and then found that several of these molecules not only bound to the protein but also either increased or decreased in amounts on the surface of cells. These chemicals, including benzaldehyde derivatives that are also used as flavorings in e-cigarettes, blocked activation of human MAIT cells by compounds produced by bacteria.
The research team then studied the effects of cigarette smoke on MAIT cells from human blood and mice and showed they reduced MAIT cell function. Mice repeatedly exposed to cigarette smoke developed symptoms of lung disease and this was worsened if also infected by influenza. Researchers found that long-term exposure to cigarette smoke altered the protection provided to mice by their MAIT cells, making them less able to fight off influenza infections and more prone to the development of COPD disease.
"We found that mice lacking MAIT cells were also protected from cigarette smoke-induced COPD, showing reduced levels of lung inflammation and no tissue deterioration in their lung's air sacs" Profesor Hansbro said. "This study demonstrates the power of collaboration and the insights we can gain with inter-disciplinary science," Professor Corbett said.
"Overall, our study reveals that components of cigarette smoke can bind to the protein MR1 and reduce the functions of protective immune cells called MAIT cells. This increases susceptibility to infections worsens progression of lung disease" Awad says. The researchers now plan to investigate exactly which MAIT cell pathways are impacted by cigarette smoke, in order to learn how to better treat COPD and other lung diseases.
Read the full paper in Journal of Experimental Medicine: Cigarette smoke components modulate the MR1-MAIT axis. DOI: 10.1084/jem.20240896
