# NLRP3 inflammasome-dependent and -independent interleukin-1β release by macrophages exposed to wear and corrosion products from CoCrMo implants

## TL;DR

This study explores how different particles and metal ions from CoCrMo implants trigger inflammation in macrophages, revealing distinct mechanisms involving NLRP3 and caspase-8.

## Contribution

The study identifies distinct pathways for IL-1β release in macrophages exposed to CoCrMo implant wear particles and metal ions, including NLRP3-dependent and -independent mechanisms.

## Key findings

- IL-1β release from Cr2O3 particles and Cr3+ is NLRP3 and caspase-1 dependent.
- CoCrMo particles and Co2+ induce NLRP3-independent IL-1β release, which is caspase-8 dependent.
- NLRP3 activation by Cr2O3 involves cathepsin B and lysosomal destabilization, while Cr3+ activation is ROS-mediated.

## Abstract

Wear particles and metal ions released from cobalt–chromium–molybdenum (CoCrMo) implants can trigger adverse local tissue reactions (ALTR) that can lead to implant failure. Identifying mechanisms involved in ALTR, particularly those underlying the initial inflammatory response elicited by wear particles (Cr2O3 and CoCrMo) and metal ions (Co2+ and Cr3+) is therefore critical. The macrophage pro-inflammatory response to CoCrMo particles, Co2+, and Cr3+ includes interleukin-1β (IL-1β) release, a process putatively linked to the NLPR3 inflammasome. However, the effects of Cr2O3 particles remain largely unknown. The objectives of this study were to determine whether IL-1β release by macrophages exposed to Cr2O3 particles (60 nm), CoCrMo particles (3.4 μm), Co2+, or Cr3+ is dependent on NLRP3 and caspase-1, whether NLRP3-dependent release is mediated by reactive oxygen species (ROS) and/or cathepsin B, and whether caspase-8 is involved when the release is NLRP3 independent. Bone marrow-derived macrophages (BMDM) from wild-type (wt), NLRP3-deficient (Nlrp3-/-), and caspase-1-deficient (Casp1-/-) mice were exposed to the particles or metal ions following priming with lipopolysaccharide. IL-1β release induced by Cr2O3 particles and Cr3+ was shown to be both NLRP3 and caspase-1-dependent. In contrast, IL-1β release induced by CoCrMo particles and Co2+ occurred independently of NLRP3, being caspase-1-independent in response to CoCrMo particles and partially caspase-1-dependent in response to Co2+. Further analysis suggested that NLRP3 inflammasome activation by Cr2O3 particles was cathepsin B dependent and mediated by lysosomal destabilization, whereas activation by Cr3+ was ROS-mediated. NLRP3-independent IL-1β release induced by CoCrMo particles or Co2+ was caspase-8 dependent. Collectively, these findings highlight the diversity and specificity of the mechanisms by which different CoCrMo implant wear particles and metal ions can induce IL-1β release in macrophages. Moreover, they suggest that targeting NLRP3, caspase-1, and/or caspase-8 could help mitigate the IL-1β-mediated component of the inflammatory response triggered by wear particles and metal ions from CoCrMo implants.