Uncovering the mechanism by which one inflammatory disease exacerbates another

The immune system has a memory, which, typically, is triggered by previous exposures to hazards like bacteria or viruses, and it is useful. When internal causes like chronic inflammation stimulate this memory, it can be harmful, prolonging incorrect immune responses.

Researchers from the University of Pennsylvania (USA), the Technical University of Dresden (Germany), the University of Bonn, the University of Edinburgh (Scotland), Radboud University (Netherlands), Democritus University of Thrace (Greece), and Shanghai Jiao Tong University (China) described the mechanism by which innate immune memory leads to increased susceptibility to one type of inflammatory disease (in this study, gum disease) to another inflammatory disease (in this study, arthritis) by altering immune cell precursor cells—hematopoietic stem and progenitor cells/HSPCs, in the bone marrow.

They demonstrated that in a mouse model, bone marrow transplant recipients were prone to more severe arthritis if the donor had inflammatory gum disease. The findings were published online on April 27, 2022, in the journal Cell titled "Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities".

George Hajishengallis, the co-corresponding author of the paper and professor of dental medicine at the University of Pennsylvania, said, "although we used periodontitis and arthritis as our models, our findings go beyond those examples. This is actually a core mechanism that is a unifying principle for the link between multiple comorbidities."

This mechanism may also prompt reconsideration of how bone marrow donors are selected, as donors who carry certain types of immune memory caused by an underlying inflammatory disease may put bone marrow transplant recipients at higher risk for inflammatory disease, these authors noted.

In a previous study, Hajishengallis collaborated with Triantafyllos Chavakis of the Technical University of Dresden and co-workers to explore the role of innate immune memory. Their findings suggest that, like the T and B cells of the adaptive immune system, the bone marrow cells of the innate immune system, such as neutrophils and macrophages, can "remember" past encounters and be more responsive when encountering new threats. They also determined how this memory is encoded, traced it back to the bone marrow, and showed that this "trained immunity" can be transferred from one organism to another through bone marrow transplantation, thus protecting the recipient from cancer through the innate immune response.

Mice with induced periodontal disease also had a more severe response to subsequent immune system challenges, evidence of trained immunity.

Researchers transplanted 200 HSPCs from the bone marrow of the mice with periodontitis into previously irradiated mice that had never had gum disease. Several months later, these mice were exposed to antibodies to collagen that can trigger arthritis.

"Mice that got HSPC transplants from mice with periodontitis had more severe arthritis than mice that received HSPC grafts from mice donors with healthy periodontium," Hajishengallis added.

Chavakis said, "the higher joint inflammation in recipient mice is due to inflammatory cells derived from periodontitis-trained donor HSPCs."

Further research revealed that signaling pathways controlled by the IL-1 receptor play a key role in this inflammatory memory. These authors found that mice lacking IL-1 receptor signaling were unable to generate the immune memory that makes recipient mice more susceptible to comorbidities.

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