Deciphering Inflammasome Activation in Gaucher Macrophages and Its Role in the Development of Multiple Myeloma

Gaucher disease (GD) is the most common lysosomal storage disease and corresponds to the accumulation of glucocerebroside in macrophages due to defective synthesis of the β-glucocerebrosidase. This lysosomal storage leads to the characteristic engorged macrophages, known as Gaucher macrophages (GMs) and contributes to the secretion of inflammatory cytokines, bone disease, splenomegaly and cytopenia typically encountered in patients with GD. Interestingly, patients with GD have an increased incidence of both polyclonal and monoclonal gammopathies with an increased risk of multiple myeloma (MM). We have recently been shown in MM that the NLRP3 inflammasome in TAMs is triggered by “frustrated phagocytosis” and represents a critical and early step in the initiation and progression of MM (Hofbauer et al., Immunity, 2021). Therefore, we hypothesize that the inflammasome is activated in GMs, and excessive production of interleukin (IL)-1β and IL-18 by macrophages promotes the development of MM. We identified subsets of pro-inflammatory macrophages in GD patients with increased transcription of inflammasome associated-markers (AIM2, CASP1, IL-1B, IL-18, and NLRP3) by single-cell RNA sequencing. We verified this inflammasome activation in GMs by immunohistochemistry and flow cytometry through detection of active caspase-1 and ASC aggregation. Mechanistically, we demonstrated in macrophages from healthy donors, that excessive addition of glucocerebroside or inhibition of β-glucocerebrosidase leads to lysosomal rupture, caspase-1 activation and secretion of IL-1β and IL-18. Furthermore, the coculture of primary isolated MM cells with GMs resulted in a significantly higher proliferation and metabolic activity of the tumour cells. Notably, blockade of inflammasome activation by MCC950 (a specific inhibitor of the NLRP3 inflammasome) results in reduced IL-1β and IL-18 secretion from ex vivo cultured GMs. These data suggest that the inflammasome is activated in GMs by disruption of the lysosomal integrity and that therapeutic inhibition of the NLRP3 inflammasome in GD patients may reduce the risk of clonal evolution of plasma cells.