Related Experiment Video
Updated: Sep 12, 2025
Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
NLRP3 inflammasome is regulated in osteoclasts through a Tmem178-dependent mechanism that restricts calcium influx
Khushpreet Kaur1, Yael Alippe1, Chun Wang1
1Division of Bone and Mineral Diseases, Washington University School of Medicine; St. Louis, MO 63110, USA.
Abstract:
Osteoclasts (OCs) differentiate from macrophages in response to RANKL. Here, we investigated the role of the NLRP3 inflammasome in mouse macrophages, with or without exposure to RANKL. Unexpectedly, we found that NLRP3 expression gradually declined during osteoclastogenesis but could be restored with LPS treatment. LPS and nigericin robustly activated this inflammasome in macrophages, as expected, but not in OCs. Mechanistically, we identified Tmem178, a protein that restrains Ca2+ release from the endoplasmic reticulum (ER) and highly expressed in OCs, as an inhibitor of this inflammasome. Notably, NLRP3 inflammasome activation was robust in OCs lacking Tmem178 or wild-type (WT) OCs exposed to high calcium concentrations. In vivo studies demonstrated that under the conditions where OCs efficiently release Ca2+ from bone, inflammasome formation was enhanced. Furthermore, deletion of Nlrp3 rescued osteopenia in Tmem178 -/- mice. Thus, we found that Tmem178 uniquely restricts Ca2+ release from ER in OCs, thereby suppressing NLRP3 inflammasome activation.
Insights
The NLRP3 inflammasome is suppressed in osteoclasts by Tmem178, which limits calcium release. Deleting NLRP3 rescues osteopenia in Tmem178-deficient mice, revealing a novel mechanism in bone homeostasis.
Area of Science:
- Immunology
- Cell Biology
- Bone Biology
Background:
- Osteoclasts (OCs) are crucial for bone remodeling and differentiate from macrophages.
- The NLRP3 inflammasome plays a role in inflammatory processes.
- Understanding inflammasome regulation in OCs is important for bone health.
Purpose of the Study:
- To investigate the role and regulation of the NLRP3 inflammasome during osteoclastogenesis.
- To identify mechanisms controlling NLRP3 inflammasome activation in OCs.
Main Methods:
- Investigated NLRP3 inflammasome expression and activation in mouse macrophages and OCs.
- Utilized LPS and nigericin stimulation.
- Identified Tmem178 as a regulator of Ca2+ release and inflammasome activity.
- Performed in vivo studies using Tmem178 knockout mice and Nlrp3 deletion.
Main Results:
- NLRP3 expression declined during osteoclastogenesis but was restored by LPS.
- NLRP3 inflammasome was activated in macrophages but not OCs.
- Tmem178, highly expressed in OCs, inhibited NLRP3 inflammasome by restraining ER Ca2+ release.
- NLRP3 inflammasome activation was enhanced in OCs with high Ca2+ or lacking Tmem178.
- Nlrp3 deletion rescued osteopenia in Tmem178-/- mice.
Conclusions:
- Tmem178 acts as a unique suppressor of the NLRP3 inflammasome in OCs.
- Tmem178 restricts Ca2+ release from the ER, thereby inhibiting NLRP3 inflammasome activation.
- This mechanism is relevant to bone homeostasis and osteopenia development.
Related Concept Videos
01:31Osteoclasts in Bone Remodeling
01:27Feedback Regulation of Calcium Concentration
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
01:16Calmodulin-dependent Signaling
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
01:17Hormones and Bone Tissue
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...
01:31Regulation of the Unfolded Protein Response
01:40Bone Remodeling