Abstract
Inflammasomes are multiprotein complexes that trigger the activation of caspase-1 and the maturation of IL-1β, which are critical for inflammation and control of pathogen infection. Although the function of inflammasomes in immune response and disease development is well studied, the molecular mechanism by which inflammasomes are activated and assembled remains largely unknown. In this study, we found that β-arrestin1, a key regulator of the G protein–coupled receptor signaling pathway, was required for nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain–containing 3 (NLRP3) and NLR family CARD domain–containing protein 4 (NLRC4) inflammasome–mediated IL-1β production and caspase-1 activation, but it had no effect on absent in melanoma 2 (AIM2) inflammasome activation. Moreover, apoptosis-associated speck-like protein containing a CARD (ASC) pyroptosome, which is ASC aggregation mediating caspase-1 activation, was also impaired in β-arrestin1–deficient macrophages upon NLRP3 or NLRC4, but not AIM2 inflammasome activation. Mechanistic study revealed that β-arrestin1 specifically interacted with NLRP3 and NLRC4 and promoted their self-oligomerization. In vivo, in a monosodium urate crystal (MSU)-induced NLRP3-dependent peritonitis model, MSU-induced IL-1β production and neutrophil flux were significantly reduced in β-arrestin1 knockout mice. Additionally, β-arrestin1 deficiency rescued the weight loss of mice upon log-phase Salmonella typhimurium infection, with less IL-1β production. Taken together, our results indicate that β-arrestin1 plays a critical role in the assembly and activation of two major canonical inflammasomes, and it may provide a new therapeutic target for inflammatory diseases.
Footnotes
This work was supported by National 973 Key Project of China Grant 2013CB530504, National 863 Project of China Grants 2012AA02A404 and 2012AA020103, National Natural Science Foundation of China Grants 31030029, 31230024, and 81361120409, National Science and Technology Major Projects of China Grants 2012ZX10002-007-003, 2013ZX10004-101-005, and 2013ZX10004-003-003, and Chinese Academy of Sciences Key Project Grant KJZD-EW-L09-3.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- AIM2
- absent in melanoma 2
- Arrb1−/−
- β-arrestin1 deficient
- ASC
- apoptosis-associated speck-like protein containing a CARD
- BMDC
- bone marrow–derived dendritic cell
- ω-3 FA
- omega-3 fatty acid
- LDH
- lactate dehydrogenase
- MSU
- monosodium urate
- NLR
- nucleotide-binding domain and leucine-rich repeat containing
- NLRC4
- NLR family CARD domain–containing protein 4
- NLRP3
- NLR family pyrin domain–containing 3
- NMDA
- N-methyl-d-aspartate
- poly(dA:dT)
- poly(deoxyadenylic-thymidylic) acid
- WT
- wild-type.
- Received August 5, 2014.
- Accepted December 5, 2014.
- Copyright © 2015 by The American Association of Immunologists, Inc.