Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome

Abstract

The NLRP3 inflammasome is a cytosolic complex that activates Caspase-1, leading to maturation of interleukin-1β (IL-1β) and IL-18 and induction of proinflammatory cell death in sentinel cells of the innate immune system. Diverse stimuli have been shown to activate the NLRP3 inflammasome during infection and metabolic diseases, implicating the pathway in triggering both adaptive and maladaptive inflammation in various clinically important settings. Here I discuss the emerging model that signals associated with mitochondrial destabilization may critically activate the NLRP3 inflammasome. Together with studies indicating an important role for Ca2+ signaling, these findings suggest that many stimuli engage Ca2+ signaling as an intermediate step to trigger mitochondrial destabilization, generating the mitochondrion-associated ligands that activate the NLRP3 inflammasome.

Keywords: NLRP3 inflammasome; calcium signaling; mitochondrial damage; mitochondrial destabilization.

Fig 1. Mechanisms of Ca²⁺ mobilization during NLRP3 inflammasome activation

NLRP3 inflammasome activators initiate Ca²⁺ signaling in a context dependent manner. GPCRs such as CaSR trigger Ca²⁺ signaling via PLC activation, IP₃ generation, and opening of the IP₃R. Alternatively, Ca²⁺ can enter via Ca²⁺ channels and pores (e.g. P2X7R, TRPM2, and pore forming toxins) or damaged membranes. Such Ca²⁺ influx can activate PLC to lead to IP₃R opening, and/or act directly on RyR, another ER resident Ca²⁺ channel. Therefore, many stimuli may converge on ER Ca²⁺ release proximal to inflammasome activation, allowing for amplification of Ca²⁺ signaling and coordination of mitochondrial Ca²⁺ uptake, dynamics, and destabilization.

Fig 2. Role of Ca²⁺ signaling during NLRP3 inflammasome activation

Ca²⁺ and cAMP may bind directly to the NLRP3 inflammasome complex to positively and negatively regulate assembly and/or activation respectively, such that the balance of Ca²⁺ and cAMP signaling determines the outcome of inflammasome activation (left). Alternatively, mitochondrial Ca²⁺ uptake (via ER Ca²⁺ release channels and mitochondrial MCU) can lead to Ca²⁺ overload and associated mitochondrial destabilization, including mROS production and induction of MPT, thus facilitating cardiolipin externalization and mtDNA release (right).

Fig 3. Activation of the NLRP3 inflammasome and the apoptosome

Following MOMP, release of cyt c from the mitochondrial intermembrane space leads to activation of the apoptosome and consequent Caspase-9-mediated apoptosis. In contrast, the NLRP3 inflammasome is activated by mitochondrial destabilization-associated cardiolipin externalization and mtDNA release, followed by Caspase-1-mediated pro-inflammatory cell death (called pyroptosis).