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Calcium-sensing receptor-mediated NLRP3 inflammasome activation in rheumatoid arthritis and autoinflammation - PubMed

  • ️Sun Jan 01 2023

Review

Calcium-sensing receptor-mediated NLRP3 inflammasome activation in rheumatoid arthritis and autoinflammation

Lina Emilia Werner et al. Front Physiol. 2023.

Abstract

The calcium-sensing receptor (CaSR) is expressed in many cell types - including immune cells and in particular circulating monocytes. Here, the receptor plays an important physiological role as a regulator of constitutive macropinocytosis. This review article provides an overview of the literature on the role of the calcium sensing receptor in the context of inflammatory processes. Special emphasis is laid upon the importance for monocytes in the context of rheumatoid arthritis. We have shown previously, that stimulation of the receptor by increased extracellular Ca2+ ([Ca2+]ex) triggers a pro-inflammatory response due to NLRP3 inflammasome assembly and interleukin (IL)-1β release. The underlying mechanism includes macropinocytosis of calciprotein particles (CPPs), which are taken up in a [Ca2+]ex-induced, CaSR dependent manner, and leads to strong IL-1β release. In rheumatoid arthritis (RA), this uptake and the resulting IL-1β release is significantly increased due to increased expression of the receptor. Moreover, increased [Ca2+]ex-induced CPP uptake and IL-1β release is associated with more active disease, while CaSR overexpression has been reported to be associated with cardiovascular complications of RA. Most importantly, however, in animal experiments with arthritic mice, increased local calcium concentrations are present, which in combination with release of fetuin-A from eroded bone could contribute to formation of CPPs. We propose, that increased [Ca2+]ex, CPPs and pro-inflammatory cytokines drive a vicious cycle of inflammation and bone destruction which in turn offers new potential therapeutic approaches.

Keywords: NLRP3 inflammasome; calciprotein particle; calcium-sensing receptor; inflammation; monocytes; rheumatoid arthritis.

Copyright © 2023 Werner and Wagner.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

Overview of the CaSR dependent mechanism of Ca2+/CPP-induced inflammasome activation in monocytes/macrophages. CaSR-induced signaling pathways important for NLRP3 inflammasome activation, are induced by coupling to G protein dimers. Signal transduction via Gq/11 induces the activation of phospholipase C (PLC), which completes the hydrolysis of phosphatidylinositol 4,5-bisphosphate in inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 leads to release of Ca2+ from intracellular calcium stores. The resulting increase in intracellular Ca2+ concentration ([Ca2+]) triggers various signal transductions and presumably contributes to the activation of the NLRP3 inflammasome. CaSR-mediated Gi/o pathway activation, which has been described in macrophages (Lee et al., 2012) but not in monocytes (Rossol et al., 2012b), leads to inhibition of adenylate cyclase (AC) and reduction of cellular cAMP level. The downregulation of cAMP diminishes its inhibitory effect on the assembly of the inflammasome, therefore allowing for its activation (blue box) (Lee et al., 2012). Activation of CaSR also contributes to constitutive macropinocytosis in monocytes/macrophages and leads to accumulation of certain lipid mediators. These lead to actin polymerization via induction of specific GTPases such as Rac1/2, resulting in Arp2/3-dependent branching of the actin network. CaSR-mediated macropinocytosis allows the uptake of calciprotein particles (CPPs) from the extracellular space. These amorphous particles are formed via binding of Ca2+ and phosphate ions (Pi) by the serum protein fetuin-A. The uptake and internalization of these particles is pivotal for the activation of the inflammasome and induce an additional increase in cytosolic [Ca2+]. The priming necessary for the assembly of the inflammasome, which is required, for example, for the provision of pro-IL-1β, ASC, and pro-caspase-1, can be mediated by cytokines in the inflammatory context, or by endogenous toll-like receptor ligands like tenascin-C (TNC) in synovitic joints in rheumatoid arthritis. Figure modified according to (Jäger et al., 2020) and created with BioRender.com.

FIGURE 2
FIGURE 2

Anatomy of healthy joints (left) and pathological changes in RA (right). The healthy joint with joint capsule, synovial membrane consistent of a cell monolayer, cartilage and bone. RA leads to thickening of the synovial membrane due to immigrating immune cells, inflammatory cytokines are released, and cartilage and bone destroyed. Enlarged cutout: situation in areas of erosive bone resorption: Misdirected activation of osteoclasts leads to increased bone resorption, and release of high concentrations of the bone components calcium, phosphate, and fetuin-A. Monocytes migrate chemotactically from blood vessels into the synovial membrane, take up CPPs, and secrete pro-inflammatory cytokines, especially IL-1β. Figure modified according to (Jäger et al., 2020) and created with BioRender.com.

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Grants and funding

This work was supported by the German Research Foundation (www.dfg.de/): UW (WA 2765/9-2) and by the Open Access Publishing Fund of Leipzig University, which is supported by the German Research Foundation within the program Open Access Publication Funding.