Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis

Abstract

Increased extracellular Ca 2+ concentrations ([Ca 2+ ] ex) trigger activation of the NLRP3 inflammasome in monocytes through calcium-sensing receptor (CaSR). To prevent extraosseous calcification in vivo, the serum protein fetuin-A stabilizes calcium and phosphate into 70-100 nm-sized colloidal calciprotein particles (CPPs). Here we show that monocytes engulf CPPs via macropinocytosis, and this process is strictly dependent on CaSR signaling triggered by increases in [Ca 2+ ] ex. Enhanced macropinocytosis of CPPs results in increased lysosomal activity, NLRP3 inflammasome activation, and IL-1β release. Monocytes in the context of rheumatoid arthritis (RA) exhibit increased CPP uptake and IL-1β release in response to CaSR signaling. CaSR expression in these monocytes and local [Ca 2+ ] in afflicted joints are increased, probably contributing to this enhanced response. We propose that CaSR-mediated NLRP3 inflammasome activation contributes to inflammatory arthritis and systemic inflammation not only in RA, but possibly also in other inflammatory conditions. Inhibition of CaSRmediated CPP uptake might be a therapeutic approach to treating RA.

An update on the regulatory mechanisms of NLRP3 inflammasome activation

“… 113 In addition, the increased extracellular Ca 2+ and phosphate induced by the formation of fetuin-A-based calciprotein particles triggers NLRP3 inflammasome activation through CaSR-mediated signaling, leading to pathological inflammation in inflammatory arthritis. 114 Taken together, these data suggest that Ca 2+ flux-induced signaling depends on another molecule/pathway to integrate sufficient signals for NLRP3 inflammasome activation. It will be important to explore further the molecular mechanisms by which signals selectively and cooperatively impact the ability of Ca 2+ flux to activate the NLRP3 inflammasome.…”

Effect of infusion irrigation with different irrigating solutions on transient receptor potential vanilloid 5 and intra-articular inflammation in a post-traumatic osteoarthritis rabbit model

“…Besides, the expression of IL-1 β and MMP3 in the synovial tissue in the CaCl 2 group was increased, while that in the MgSO 4 group was decreased. The increase of extracellular Ca 2 + concentration triggers the activation of NLRP3 inflammatory bodies in monocytes through the calcium-sensitive receptor (CaSR) and promotes the release of IL-1 β, which aggravates the intra-articular inflammation [28]. However, MgSO 4 is a natural antagonist of Ca 2 + influx, can inhibit the expression of TRPV5 [25,29], and can block endothelial IL-1 β secretion [30].…”

Calciprotein Particles

“…Indeed, knockdown of the MSR1 gene or blockade of the MSR1 receptor in macrophages diminishes the internalization of secondary CPPs without affecting the internalization of primary CPPs. 53 , 54 Furthermore, the CaSR (calcium-sensing receptor) is expressed on a variety of vascular cells, including ECs, smooth muscle cells, and monocytes 56 , 57 and offers an alternative route for CPP internalization. Blood monocytes internalize secondary CPPs via the CaSR in a Ca 2+ concentration-dependent manner, but independently of PO 4 3− .…”