Dissecting the phenotypic and functional heterogeneity of mouse inflammatory osteoclasts by the expression of Cx3cr1

Bone destruction relies on interactions between bone and immune cells. Bone-resorbing osteoclasts (OCLs) were recently identified as innate immune cells activating T cells toward tolerance or inflammation. Thus, pathological bone destruction not only relies on increased osteoclast differentiation, but also on the presence of inflammatory OCLs (i-OCLs), part of which express Cx3cr1. Here, we investigated the contribution of mouse Cx3cr1(+) and Cx3cr1(neg) i-OCLs to bone loss. We showed that Cx3cr1(+) and Cx3cr1(neg) i-OCLs differ considerably in transcriptional and functional aspects. Cx3cr1(neg) i-OCLs have a high ability to resorb bone and activate inflammatory CD4(+) T cells. Although Cx3cr1(+) i-OCLs are associated with inflammation, they resorb less and have in vitro an immune-suppressive effect on Cx3cr1(neg) i-OCLs, mediated by PD-L1. Our results provide new insights into i-OCL heterogeneity. They also reveal that different i-OCL subsets may interact to regulate inflammation. This contributes to a better understanding and prevention of inflammatory bone destruction.