The role of NLRP3 and AIM2 in inflammasome activation during Brucella abortus infection

Abstract

The innate immune system is essential for the detection and elimination of bacterial pathogens. Upon inflammasome activation, caspase-1 cleaves pro-IL-1β and pro-IL-18 to their mature forms IL-1β and IL-18, respectively, and the cell undergoes inflammatory death termed pyroptosis. Here, we reviewed recent findings demonstrating that Brucella abortus ligands activate NLRP3 and AIM2 inflammasomes which lead to control of infection. This protective effect is due to the inflammatory response caused by IL-1β and IL-18 rather than cell death. Brucella DNA is sensed by AIM2 and bacteria-induced mitochondrial reactive oxygen species is detected by NLRP3. However, deregulation of pro-inflammatory cytokine production can lead to immunopathology. Nervous system invasion by bacteria of the genus Brucella results in an inflammatory disorder termed neurobrucellosis. Herein, we discuss the mechanism of caspase-1 activation and IL-1β secretion in glial cells infected with B. abortus. Our results demonstrate that the ASC inflammasome is indispensable for inducing the activation of caspase-1 and secretion of IL-1β upon infection of astrocytes and microglia with Brucella. Moreover, our results demonstrate that secretion of IL-1β by Brucella-infected glial cells depends on NLRP3 and AIM2 and leads to neurobrucellosis. Further, the inhibition of the host cell inflammasome as an immune evasion strategy has been described for bacterial pathogens. We discuss here that the bacterial type IV secretion system VirB is required for inflammasome activation in host cells during infection. Taken together, our results indicate that Brucella is sensed by ASC inflammasomes mainly NLRP3 and AIM2 that collectively orchestrate a robust caspase-1 activation and pro-inflammatory response.

Keywords: AIM2; Brucella; Dendritic cells; Inflammasome; NLRP3; Neurobrucellosis.

Figure 1. Working model of AIM2 and NLRP3 inflammasome activation by B. abortus

B. abortus PAMPs trigger MAPK and NF-κB signaling pathways in a MyD88 and IRAK-4-dependent manner which is important in the induction of the first signal and generate inactive form of pro-IL-1β. B. abortus ensures its survival by forming the Brucella-containing vacuole (BCV), which traffics along the endocytic pathway. It is believed that DNA can be released by the type IV secretion system or by the action of GBPs. GBPs mediate bacterial killing resulting in abundant release of bacterial DNA for recognition by AIM2. The released bacterial DNA is then sensed by the cytosolic AIM2 inflammasome. In parallel, infection of host cells with B. abortus can generate ER stress and consequent activation of the sensor IRE1. This sensor induces an increase in mitochondrial ROS and culminates in the release of mitochondrial DAMPs. NLRP3 and AIM2 activation triggers assembly of inflammasomes containing ASC and caspase-1, leading to pro-IL-1β processing and secretion of mature IL-1β.

Figure 2. Brucella activation of CNS innate immunity

Brucella invades the CNS and triggers two signals in glial cells. A Brucella PAMP (i.e. lipoproteins) interacts with TLR2 and through the recruitment of MYD88 and Mal/TIRAP induces the activation of the NF-kB pathway. The translocation of NF-kB to the nucleus of glial cells, both astrocytes and microglia, induces the transcription and secretion of TNF and IL-6. These cytokines have an autocrine effect on glial cells and produces astrogliosis (proliferation and apoptosis simultaneously of astrocytes) and secretion of MMP-9. On the other hand, the interaction with TLR2 triggers the transcription of pro-IL-1β. A second signal results in the assembly of the ASC inflammasomes NLRP3 and AIM2. These in turn activate caspase-1 that induces the proteolytic maturation of the secreted form of IL-1β. This cytokine activates microvascular endothelium of the blood-brain barrier and results in the recruitment of leukocytes to the CNS.