Metabolic

Immune responses in persistent ailments may be triggered by tissue stiffness

Stiffness in our tissues creates tension in our cells. Research from the Buck Institute, University Health Network (University of Toronto), Stanford University, and the University of Alberta shows that stiffness affects the innate immune system by increasing its metabolism. The results suggest that cell tension is likely to trigger an inflammatory loop that contributes to the development of chronic aging diseases. Buck Associate Professor Dan Winer, MD, and colleagues publish a new look at how the immune system works, opportunities for new immunotherapeutic agents, and a call for scientists to reconsider the way they research in Cell Reports.

While stiffness is a recognized factor in acute infections (think swollen lymph glands or swelling after a cut), Winer’s particular focus is on how stiffness arising from the environment affects immune cells. “While viruses and bacteria play key roles in triggering an immune response, we think the forces surrounding cells are an extremely important piece of the puzzle that affects immunity,” he said. “The stiffness of our tissues and the resulting changes in cellular tension change with most diseases and with aging itself,” said Winer. “This work provides support for a new way of thinking about how the immune system works, suggesting that mechanical force activates and likely controls immunology in acute and chronic disease as it prepares the immune system in the face of danger.”

Winer and his team, led by Mainak Chakraborty, MSc, research fellow at the University Health Network in Toronto, and Sue Tsai, former postdoctoral fellow in the laboratory, now assistant professor at the University of Alberta, cultured dendritic cells (DCs), a component of the innate immune system, which coordinates an immune response from the mouse bone marrow and spleen with varying degrees of physiological rigidity. “DCs grown under physiological resting stiffness showed decreased proliferation, activation, and cytokine production compared to cells grown under high stiffness that mimicked fibroinflammatory disease,” said Chakraborty. “DCs with high stiffness showed increased activation and flow in major glucose metabolic pathways,” added Tsai. “In models of autoimmune diabetes and tumor immunotherapy, cellular tension has caused DCs to trigger an adaptive immune system response that is specific and secondary to infection or injury.” The results were not limited to mouse DCs, as human DCs also showed increased activity markers under higher voltage.

The researchers identified the hippo signaling molecule TAZ as an important factor influencing DC metabolism and the function of the innate immune response under tension. Winer says the finding is significant because a laboratory at the University of California at Los Angeles recently showed that the same pathway favors the effects of tension in the adaptive immune system. “This appears to be a critical way to capture the environmental forces in both arms of the immune system,” said Winer. “Mechanoimmunology has not yet been adequately researched. We hope that our work will advance this emerging field and lead to the development of new immunotherapies that allow the immune system to function normally under the many conditions that alter tissue stiffness. ”

Great impact on deadly diseases and chronic diseases of old age

According to Winer, there are a number of diseases that are likely to be affected by the influence of tissue stiffness on the immune system. “Heart disease, cancer and lower lung disease are among the leading causes of death in the US,” he said. “Computer algorithms from our study show that all of these conditions are strongly modulated by genes or protein interactions that are induced by tensions in the immune system. Those studying these diseases should consider this finding. ”

Winer notes that tissue stiffness is a well-known phenomenon associated with aging (for example, the stiffness of the lungs and their blood vessels can double with age), and the interaction with the immune system is likely to lead to low-grade chronic ones Inflammation contributes that drives many of the diseases of aging. “The tension due to stiffness boosts metabolism and cytokine production in DCs, potentially contributing to what is now known as inflammation.” Winer says his lab plans to study mechanoimmunology in aging mice and related to certain diseases.

Winer says the genes that are activated by cell voltage are potential targets for immunotherapeutic drugs, which is another focus of his lab. He says there are now techniques (via an add-on to magnetic resonance imaging or ultrasound) that enable the imaging of stresses in certain tissues and organs. Winer said the ability to track tension could be a biomarker of aging and make testing new drugs easier.

One final note for researchers: be careful when cultivating on plastic!

Almost as important as the results of this study, Winer urges researchers to consider changing the way they cultivate immune cells. He says the vast majority of scientists have been using plastic sheets to grow their cells for decades, which exerts tension a thousand times greater than what a cell feels in the body. “Many immune cells need to anchor themselves in the shell, and the stiffness of the plastic exerts a supraphysiological force on the cells,” he said. The Winer team grows immune cells on soft silicone gels that have been treated to closely mimic the physiology in the body. “We believe that the introduction of new research cultivation techniques in immunology could better mimic physiology in the body.”

reference
Winer D et al. Mechanical stiffness controls the metabolism and function of dendritic cells. Cell reports. DOI: 10.1016 / j.celrep.2020.108609

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