β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression

As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macro- phages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (b2m) as a driver in initiating inflammation in myeloma-associated macro- phages (MAMs). Lysosomal accumulation of phagocytosed b2m promotes b2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1b (IL-1b) and IL-18. This process depends on activation of the NLRP3 inflammasome after b2m accumulation, as macrophages from NLRP3-deficient mice lack efficient b2m-induced IL-1b production. Moreover, depletion or silencing of b2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by b2m-induced inflammasome signaling. Our results provide mechanistic evidence for b2m’s role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a poten- tial therapeutic approach in MM.