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

Hofbauer D, Mougiakakos D, Broggini L, Zaiss M, Büttner-Herold M, Bach C, Spriewald B, Neumann F, Bisht S, Nolting J, Zeiser R, Hamarsheh S, Eberhardt M, Vera J, Visentin C, De Luca CMG, Moda F, Haskamp S, Flamann C, Böttcher M, Bitterer K, Völkl S, Mackensen A, Ricagno S, Bruns H (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Immunity Elsevier

Book Volume: 54

Pages Range: 1772-1787.e9

Journal Issue: 8

DOI: 10.1016/j.immuni.2021.07.002

Abstract

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.

Authors with CRIS profile

Daniel Hofbauer Department of Medicine 5 – Haematology and Oncology Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie Mario Zaiss Department of Medicine 3 – Rheumatology and Immunology Maike Büttner-Herold Department of Nephropathology Christian Bach Department of Medicine 5 – Haematology and Oncology Bernd Spriewald Medizinische Fakultät Martin Eberhardt Department of Dermatology Julio Vera González Professur für Tumorimmunologie (Schwerpunkt Systembiologie) Stefan Haskamp Lehrstuhl für Humangenetik Cindy Flamann Department of Medicine 5 – Haematology and Oncology Martin Böttcher Department of Medicine 5 – Haematology and Oncology Simon Völkl Department of Medicine 5 – Haematology and Oncology Andreas Mackensen Lehrstuhl für Innere Medizin V Heiko Bruns Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Università degli studi di Milano IT Italy (IT) Foundation of the Carlo Besta Neurological Institute (IRCCS) IT Italy (IT) Universitätsklinikum Bonn DE Germany (DE) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Albert-Ludwigs-Universität Freiburg DE Germany (DE)

How to cite

APA:

Hofbauer, D., Mougiakakos, D., Broggini, L., Zaiss, M., Büttner-Herold, M., Bach, C.,... Bruns, H. (2021). β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression. Immunity, 54(8), 1772-1787.e9. https://doi.org/10.1016/j.immuni.2021.07.002

MLA:

Hofbauer, Daniel, et al. "β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression." Immunity 54.8 (2021): 1772-1787.e9.

BibTeX: Download