Local immune cell contributions to fracture healing in aged individuals – A novel role for interleukin 22

• Published in: Experimental & molecular medicine 2022, 54(0), , pp.1-15
• Main Authors: Bucher, Christian H., Berkmann, Julia C., Burkhardt, Lisa-Marie, Paschke, Carolin, Schlundt, Claudia, Lang, Annemarie, Wolter, Angelique, Damerau, Alexandra, Geissler, Sven, Volk, Hans-Dieter, Duda, Georg N., Schmidt-Bleek, Katharina
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/106; 13/21; 13/31; 59; 631/250/127/1213; 631/250/808; 631/80/304; 64/60; 692/699/578; 82/47; Adaptive immunity; Aging; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Bone growth; Bone healing; Cell activation; Cell signaling; Chemokine receptors; Cytokines; Cytokines - metabolism; Fracture Healing - immunology; Fractures; Geriatrics; Immune system; Inflammation; Interleukin 22; Interleukins - immunology; Interleukins - metabolism; Long bone; Medical Biochemistry; Mice; Microbiomes; Molecular Medicine; Osteogenesis; Osteoprogenitor cells; Progenitor cells; Proteins; Regeneration; Stem Cells; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-022-00834-9

With increasing age, the risk of bone fractures increases while regenerative capacity decreases. This variation in healing potential appears to be linked to adaptive immunity, but the underlying mechanism is still unknown. This study sheds light on immunoaging/inflammaging, which impacts regenerative processes in aging individuals. In an aged preclinical model system, different levels of immunoaging were analyzed to identify key factors that connect immunoaged/inflammaged conditions with bone formation after long bone fracture. Immunological facets, progenitor cells, the microbiome, and confounders were monitored locally at the injury site and systemically in relation to healing outcomes in 12-month-old mice with distinct individual levels of immunoaging. Bone tissue formation during healing was delayed in the immunoaged group and could be associated with significant changes in cytokine levels. A prolonged and amplified pro-inflammatory reaction was caused by upregulated immune cell activation markers, increased chemokine receptor availability and a lack of inhibitory signaling. In immunoaged mice, interleukin-22 was identified as a core cell signaling protein that played a central role in delayed healing. Therapeutic neutralization of IL-22 reversed this specific immunoaging-related disturbed healing. Immunoaging was found to be an influencing factor of decreased regenerative capacity in aged individuals. Furthermore, a novel therapeutic strategy of neutralizing IL-22 may successfully rejuvenate healing in individuals with advanced immune experiences. Aging: immune protein’s role in delayed bone fracture healing Neutralizing a key cytokine, a signaling protein affecting the immune system could rejuvenate the healing process following prolonged inflammatory responses to bone fractures in elderly patients. Healing patterns vary widely in the elderly following injuries such as bone fractures, and scientists now believe that a patient’s individual innate and adaptive immune profile directly affects the healing process. A short-lived pro-inflammatory response is needed to kickstart healthy healing, but a longer-lasting response can be damaging. In experiments on aged mouse models, the team led by Katharina Schmidt-Bleek at the Julius Wolff Institute in Berlin, Germany, demonstrated that high levels of the cytokine interleukin-22 impaired bone regeneration. Elevated interleukin-22 levels resulted from chronically elevated inflammation and inflammaging, prevalen