Steroid Curbs Chronic Lung Inflammation Without Weakening Immune Defenses
Nontuberculous mycobacterial infections have become an increasing concern for people with chronic lung disease, in part because the infections can linger despite months of antibiotic treatment. Among the most common culprits is Mycobacterium avium, which can trigger persistent inflammation in the lungs and leave patients with ongoing symptoms even when antimicrobial therapy is underway.
Now, researchers from Trinity College Dublin and St. James’s Hospital report that dexamethasone, a widely used anti-inflammatory steroid, reduced inflammatory signaling in human macrophages infected with M. avium without compromising the cells’ ability to control bacterial growth. The study, “Dexamethasone Reduces Glycolysis and Inflammation in Human Macrophages Infected With Mycobacterium avium Without Compromising Bacterial Control,” was published in The Journal of Infectious Diseases.
The findings point to a possible host-directed strategy for nontuberculous mycobacterial disease—one aimed not at killing the bacteria directly, but at limiting the damaging inflammation that can accompany chronic infection. “Our study suggests that it may be possible to fine-tune this response by reducing damaging inflammation while still preserving the immune defenses that help control infection,” said Donal Cox, PhD, senior author of the research at Trinity College Dublin.
To test that idea, the team studied human monocyte-derived macrophages—immune cells that serve as a first line of defense against infection. The cells were treated with dexamethasone before being infected with M. avium subsp. hominissuis 104. The researchers then used real-time metabolic flux analysis to measure glycolysis and oxygen consumption, RT-qPCR to assess metabolic and antimicrobial gene expression, colony-forming unit assays to measure bacterial burden, and ELISA assays to quantify inflammatory cytokines.
The study showed that M. avium infection drove a glycolytic response in macrophages, but dexamethasone dampened that metabolic shift. The steroid reduced glycolytic proton efflux and lowered expression of glycolysis-associated enzymes, including PFKFB3, GAPDH, and PKM2, while leaving oxygen consumption unchanged. Importantly, dexamethasone did not increase the recoverable bacterial burden over 120 hours, according to the authors.
The anti-inflammatory effects were broad. Dexamethasone significantly reduced production of TNF, IL-6, IL-8, and IL-1β in infected macrophages, and at the higher dose abrogated induction of IL-10, the authors report. It also did not alter the expression of several NADPH oxidase complex genes, supporting the authors’ conclusion that key antimicrobial functions may be preserved. The paper stated that the findings support “further investigation of dexamethasone as a potential host-directed strategy to limit inflammation while preserving host defense in nontuberculous mycobacterial disease.”
“Current treatment strategies for NTM disease focus primarily on killing the bacteria,” added Cox. “However, inflammation itself can contribute significantly to symptoms and tissue damage in patients, so finding ways to control inflammation without impairing antimicrobial innate immunity offers a potential gateway to much more effective therapies.”
The authors cautioned that the work was performed in macrophages from healthy donors and used a single M. avium strain, so the results will need to be validated in models that better reflect patients with NTM disease, including alveolar macrophages, macrophages from susceptible patients, and clinical M. avium isolates. Future studies will also need to test steroid treatment after infection and in combination with antimycobacterial therapy before dexamethasone can be considered as an adjunctive approach for chronic NTM lung disease.
