| Autor: |
Heiko Bruns, Stefano Ricagno, Cindy Flamann, Shaima’a Hamarsheh, Frank Neumann, Andreas Mackensen, Katrin Bitterer, Maike Büttner-Herold, Cristina Visentin, Robert Zeiser, Christian Bach, Dimitrios Mougiakakos, Stefan Haskamp, Daniel Hofbauer, Martin Böttcher, Savita Bisht, Chiara De Luca, Fabio Moda, Martin Eberhardt, Luca Broggini, Bernd M. Spriewald, Julio Vera, Mario M. Zaiss, Jens Nolting, Simon Völkl |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Immunity. 54:1772-1787.e9 |
| ISSN: |
1074-7613 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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