Gout is a chronic arthritis caused by the deposition of poorly soluble monosodium urate monohydrate (MSU) crystals in peripheral joints. Resident macrophages initiate inflammation in response to MSU mediated by NF-κB nuclear translocation and NLRP3 inflammasome activation. We investigated the role of CD44, a transmembrane receptor, in mediating MSU phagocytosis by macrophages. We used an antibody that sheds the extracellular domain (ECD) of CD44 to study the role of the receptor and its associated protein phosphatase 2A (PP2A) in macrophage activation. We also studied the significance of CD44 in mediating MSU inflammation in-vivo. Cd44−/− BMDMs showed reduced MSU phagocytosis, LDH release, IL-1β expression and production compared to Cd44+/+ BMDMs. Elevated CD44 staining was detected intracellularly and CD44 colocalized with α-tubulin as a result of MSU exposure and ECD-shedding reduced MSU phagocytosis in murine and human macrophages. Anti-CD44 antibody treatment reduced NF-κB p65 subunit nuclear levels, IL-1β expression, pro-IL-1β and IL-8 production in MSU stimulated THP-1 macrophages (p < 0.01). The effect of the antibody was mediated by an enhancement in PP2A activity. CD44 ECD-shedding reduced the conversion of procaspase-1 to active caspase-1, caspase-1 activity and resultant generation of mature IL-1β in macrophages. Neutrophil and monocyte influx and upregulated production of IL-1β was evident in wildtype mice. MSU failed to trigger neutrophil and monocyte recruitment in Cd44−/− mice and lower IL-1β levels were detected in peritoneal lavages from Cd44−/− mice (p < 0.01). Anti-CD44 antibody treatment reduced neutrophil and monocyte recruitment and resulted in reduced lavage IL-1β levels in the same model. CD44 plays a biologically significant role in mediating phagocytosis of MSU and downstream inflammation and is a novel target in gout treatment.
Bousoik, E., Qadri, M. & Elsaid, K.A. CD44 Receptor Mediates Urate Crystal Phagocytosis by Macrophages and Regulates Inflammation in A Murine Peritoneal Model of Acute Gout. Sci Rep 10, 5748 (2020). https://doi.org/10.1038/s41598-020-62727-z
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