Immunity
Volume 54, Issue 8, 10 August 2021, Pages 1772-1787.e9
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Article
β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression

https://doi.org/10.1016/j.immuni.2021.07.002Get rights and content
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Highlights

  • β2m that accumulates in multiple myeloma (MM) is ingested by MM-associated macrophages

  • β2m uptake leads to β-fibril aggregation, lysosomal rupture, and inflammasome activation

  • β2m contributes to inflammation in MM via IL-1β and IL-18 secretion

  • Inhibition of NLRP3 delays onset and reduces severity of MM in preclinical models

Summary

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 (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m 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 β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m’s role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.

Keywords

tumor-associated macrophages
macrophages
multiple myeloma
inflammation
NLRP3
phagocytosis

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These authors contributed equally

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