Immune and repair responses in joint tissues and lymph nodes after knee arthroplasty surgery in mice.

The importance of a local tissue immune response in healing injured tissues such as skin and lung is well established. Little is known about whether sterile wounds elicit lymph node (LN) responses and inflammatory responses after injury of musculoskeletal tissues that are mechanically loaded during the repair response. We investigated LN and tissue immune responses in a tibial implant model of joint replacement surgery where wounded tissue is subjected to movement and mechanical loading postoperatively. Draining inguinal and iliac LNs expanded postoperatively, including increases in regulatory T cells and activation of a subset of T cells. Thus, tissue injury was actively sensed in secondary lymphoid organs, with the potential to activate adaptive immunity. Joint tissues exhibited three temporally distinct immune response components, including a novel interferon (IFN) response with activation of signal transducer and activator of transcription (STAT) and interferon regulatory factor (IRF) pathways. Fibrovascular tissue formation was not associated with a macrophage type 2 (M2) reparative immune response, but instead with delayed induction of interleukin-1 family (IL-1β, IL-33, IL-36), IL-17, and prostaglandin pathway genes concomitant with transforming growth factor (TGF)-β and growth factor signaling, fibroblast activation, and tissue formation. Tissue remodeling was associated with activity of the HOX antisense intergenic RNA (HOTAIR) pathway. These results provide insights into immune responses and regulation of tissue healing after knee arthroplasty that potentially can be used to develop therapeutic strategies to improve healing, prevent arthrofibrosis, and improve surgical outcomes. © 2021 American Society for Bone and Mineral Research (ASBMR).