Rewired Inflammatory Macrophages May Offer Osteoarthritis Target

Researchers have identified a group of inflammatory macrophages that drive osteoarthritis by sustaining inflammation in the synovium – a layer of connective tissue within joints – and show that they can target these immune cells to treat the disease in mice. Their work elucidates the role of macrophages in the progression of this inflammatory disorder and offers a promising therapeutic approach for further study. Osteoarthritis continues to be a leading cause of pain and disability worldwide. Over time, studies have pointed to inflammation in the synovium as a central contributor to the progression of the disease. Within these tissues, immune cells circulate and cultivate an inflammatory environment that damages cartilage and disrupts the normal structure of bone. However, more research is needed to understand how immune cells drive synovial inflammation, as well as which molecular players might offer the best targets for therapies. Seeking insight, Rui Peng and colleagues employed single-cell RNA sequencing to study the immune cell landscape in mouse synovial tissues and samples from patients with osteoarthritis. They discovered that an inflammatory group of macrophages expressing the CD74 protein expanded and gathered at the interface between synovial tissues and cartilage. Further work showed that CD74 interacted with an enzyme named ENO2, which coaxed the cells toward an inflammatory and metabolically hyperactive state. Peng et al. then developed lipid nanoparticles loaded with silencing RNA that targets CD74. The particles homed in on CD74-bearing macrophages and calmed their inflammatory activities in vitro, and relieved synovial inflammation and disease progression in mice. "Beyond [osteoarthritis], this targeted nanotherapeutic platform holds broader implications for other chronic metaflammatory disorders driven by macrophage metabolic rewiring," the authors conclude.