| First Author | Hofbauer D | Year | 2021 |
| Journal | Immunity | Volume | 54 |
| Issue | 8 | Pages | 1772-1787.e9 |
| PubMed ID | 34289378 | Mgi Jnum | J:321304 |
| Mgi Id | MGI:6740318 | Doi | 10.1016/j.immuni.2021.07.002 |
| Citation | Hofbauer D, et al. (2021) beta2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression. Immunity 54(8):1772-1787.e9 |
| abstractText | As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (beta2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed beta2m promotes beta2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1beta (IL-1beta) and IL-18. This process depends on activation of the NLRP3 inflammasome after beta2m accumulation, as macrophages from NLRP3-deficient mice lack efficient beta2m-induced IL-1beta production. Moreover, depletion or silencing of beta2m 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 beta2m-induced inflammasome signaling. Our results provide mechanistic evidence for beta2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM. |
