Macrophages drive the inflammatory phase in experimental osteoarthritis

Montgomery, A.; Fahy, N.; Hamilton, S.; Eckman, B.; De Almeida, L.; Ishihara, S.; Mayr, M. G.; Chen, S.-Y.; Gadhvi, G.; Cuda, C.; Malfait, A.-M.; Bastiaansen-Jenniskens, Y.; Winter, D. R.

doi:10.1101/2020.05.28.122408

bioRxiv · 10.1101/2020.05.28.122408

Macrophages drive the inflammatory phase in experimental osteoarthritis

Montgomery, A.·Fahy, N.·Hamilton, S.·Eckman, B.·De Almeida, L.·Ishihara, S.·Mayr, M. G.·Chen, S.-Y.·Gadhvi, G.·Cuda, C.·Malfait, A.-M.·Bastiaansen-Jenniskens, Y.·Winter, D. R.

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Abstract

Macrophages fulfill critical functions in maintaining tissue homeostasis in steady-state, as well as in inflammation and immune response. Inflammation is not considered a major driver of osteoarthritis (OA), but macrophages have been implicated in its pathogenesis. Here, we use two mouse models of experiment OA - collagenase-induced osteoarthritis (CIOA) and destabilization of the medial meniscus (DMM) - to quantify the immune cell infiltration into the knee joint during the early stages of disease. We find that the peak of inflammation occurs at day 3 in CIOA and is characterized by a transitory increase in neutrophils and monocytes and a longer-lived expansion of synovial macrophages. Macrophage sub-populations are disproportionally expanded with CX3CR1+ cells accounting for a larger proportion of the macrophage compartment. Transcriptional profiling demonstrates that synovial macrophages up-regulate inflammatory genes coinciding with peak inflammation and down-regulate genes associated with homeostasis and tissue-residence. Female mice exhibit a similar expansion of macrophages post-CIOA indicating that the inflammatory phase is not sex-specific. Finally, we find day 7 post-DMM is also characterized by increases in neutrophil, monocyte, and macrophage sub-population numbers. These results support a role for macrophages in early stages of OA through driving the inflammatory phase. Further investigation may elucidate potential targets for the prevention or attenuation of OA-associated cartilage damage.

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Montgomery, A., Fahy, N., Hamilton, S., Eckman, B., De Almeida, L., Ishihara, S., Mayr, M. G., Chen, S.-Y., Gadhvi, G., Cuda, C., Malfait, A.-M., Bastiaansen-Jenniskens, Y., Winter, D. R.. 2020-05-31. Macrophages drive the inflammatory phase in experimental osteoarthritis. https://doi.org/10.1101/2020.05.28.122408

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