β 2 -Microglobulin - A Trigger for NLRP3 Inflammasome Activation in Tumor-Associated Macrophages Promoting Multiple Myeloma Progression

As significant constituents of the tumor microenvironment in multiple Myeloma (MM), pro-inflammatory macrophages are key promoters of disease progression, bone destruction, and immune-impairment. Consequently, the identification of endogenous mediators of these inflammatory processes can open novel therapeutic avenues against major pathological features of MM. Here, we identify beta-2-microglobulin (β2m) as an important driver in the initiation of inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m in patient-derived MAMs promoted β2m amyloid aggregation, resulting in lysosomal rupture and ultimately in the production of active interleukin (IL)-1β and IL-18. Interestingly, this process strictly depended on the activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lacked efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogated inflammasome activation in a murine MM model. Finally, we demonstrate that specific disruption of NLRP3 or IL-18 diminished tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Taken together our results provide novel mechanistic evidence for β2m’s role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 is a potential novel therapeutic approach to combat this severe malignancy.