Researchers from the University of Pennsylvania’s School of Dental Medicine, alongside international collaborators, have uncovered a surprising link between “trained” immunity and increased bone loss in experimental models of two chronic inflammatory diseases: periodontitis and arthritis. Published in Developmental Cell, this study sheds light on the complex implications of manipulating the innate immune system for therapeutic purposes.
For decades, clinical research has primarily targeted the adaptive immune system, which “remembers” previous threats to defend the body more effectively against repeated infections. In contrast, the innate immune system was long believed to lack memory, serving only as the body’s first line of defense with no ability to respond more strongly to subsequent exposures. However, this notion has been increasingly challenged in recent years.
George Hajishengallis, a professor at Penn Dental Medicine, highlights how recent studies have demonstrated that the innate immune system can, in fact, “remember” previous assaults—a phenomenon known as trained immunity or TRIM. While TRIM has shown promise in enhancing the body’s response to infections and even providing anti-tumor benefits, its impact on chronic diseases has remained unclear.
In their study, Hajishengallis and his collaborators, including Triantafyllos Chavakis from Dresden University of Technology, used ß-glucan—a compound found in certain fungi—to induce TRIM in animal models of periodontitis and arthritis. They found that TRIM primed osteoclast precursors, cells that break down bone, to respond more readily to inflammatory challenges like arthritis. This priming increased bone loss in these models, underscoring the potentially harmful side effects of enhanced immune responses.
While the researchers determined that ß-glucan itself does not directly cause bone loss, the presence of a secondary inflammatory trigger—such as arthritis or periodontitis—was necessary for the adverse effects to manifest. This finding supports the idea that trained immunity creates a state of heightened preparedness, which can be beneficial in some contexts but harmful in others, depending on the inflammatory challenges faced.
Importantly, the results suggest that the functional outcome of TRIM depends on the broader context in which it emerges. In some instances, such as cancer or infections, trained immunity may be protective. In contrast, in inflammatory bone diseases, it could exacerbate symptoms and accelerate disease progression.
“The double-edged sword nature of TRIM is crucial when considering its potential in therapeutic applications,” says Hajishengallis. As TRIM-based therapies move forward, understanding the precise mechanisms that govern its outcomes will be vital to harnessing its full potential without inadvertently worsening disease outcomes.
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