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

Abstract

The innate immune system is essential for 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 leads to control of infection. This protective effect is due to 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 proinflammatory 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 proinflammatory response.

Caspase-1 and Caspase-11 Mediate Pyroptosis, Inflammation, and Control of Brucella Joint Infection

“…The ASC-dependent inflammasomes, AIM2 and NLRP3, are known to recognize Brucella and restrict B. abortus splenic burdens during chronic infection (29,31). Surprisingly, AIM2 and NLRP3 were dispensable for control of joint infection.…”

“…Brucella infection in macrophages activates the canonical inflammasome cytosolic sensors: NLR family, pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2). Studies have shown that the Brucella type IV secretion system and mitochondrial damage can stimulate NLRP3, while Brucella DNA activates the AIM2 inflammasome pathway (29)(30)(31). Following stimulation of the NLRP3 or AIM2 sensors and subsequent cleavage of caspase-1, active caspase-1 proteolytically cleaves IL-1␤ and IL-18 into their functional/secreted forms.…”

“…Following stimulation of the NLRP3 or AIM2 sensors and subsequent cleavage of caspase-1, active caspase-1 proteolytically cleaves IL-1␤ and IL-18 into their functional/secreted forms. IL-1R and IL-18 are known to restrict Brucella burdens during chronic Brucella infection but may also lead to immunopathology, as they play a proinflammatory role in rheumatoid arthritis (29,(31)(32)(33). While NLRP3, AIM2, caspase-1, and caspase-11 are protective against chronic systemic Brucella infection in vivo (29), there are multiple studies indicating that NLRP3 and/or AIM2 contributes to pathology in autoreactive arthritis models (28,34,35).…”

Molecular mechanisms of inflammasome signaling

“…The AIM2 inflammasome provides immune surveillance for a subset of bacteria, including Francisella tularensis, 247,248 Streptococcus pneumoniae, 249,250 Mycobacterium species, [251][252][253] L. monocytogenes, [254][255][256][257][258] C. muridarum, 159 Porphyromonas gingivalis, 259 and Brucella abortus, 260,261 and the dsDNA viruses CMV and vaccinia virus. 248 The AIM2 inflammasome is also activated upon infection with the malaria parasite Plasmodium 262 and the fungal pathogen A. fumigatus.…”

Dendritic cells in autoimmunity, infections, and cancer

“…Motran et al review the mechanisms involved in the regulation of DC function by parasites (8). In addition, Marim et al discuss the mechanisms involved in the control of caspase-1 activation and IL-1 production by Brucella abortus , and its role in the establishment of chronic infection and immunopathology (9). …”