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.

β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression / D. Hofbauer, D. Mougiakakos, L. Broggini, M. Zaiss, M. Büttner-Herold, C. Bach, B. Spriewald, F. Neumann, S. Bisht, J. Nolting, R. Zeiser, S. Hamarsheh, M. Eberhardt, J. Vera, C. Visentin, C.M.G. De Luca, F. Moda, S. Haskamp, C. Flamann, M. Böttcher, K. Bitterer, S. Völkl, A. Mackensen, S. Ricagno, H. Bruns. - In: IMMUNITY. - ISSN 1074-7613. - (2021), pp. 1-26. [Epub ahead of print] [10.1016/j.immuni.2021.07.002]

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

L. Broggini;C. Visentin;S. Ricagno
Penultimo
;
2021

Abstract

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.
tumor-associated macrophages; macrophages; multiple myeloma; inflammation; NLRP3; phagocytosis;
Settore BIO/10 - Biochimica
Settore MED/04 - Patologia Generale
20-lug-2021
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/858932
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