TLR9 is required for MAPK/NF-κB activation but does not cooperate with TLR2 or TLR6 to induce host resistance to <i>Brucella abortus</i>

Gomes, Marco Túlio R.; Campos, Priscila C.; Pereira, Guilherme de Sousa; Bartholomeu, Daniella Castanheira; Splitter, Gary A.; Oliveira, Sérgio C.

doi:10.1189/jlb.4a0815-346r

Cited by 47 publications

(44 citation statements)

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“…The recognition of B. abortus by innate immune receptors results in the activation of different signaling pathways, culminating in the expression of several proinflammatory genes . We next assessed the potential role of NLRP12 in regulating NF‐κB and MAPK signaling pathways in BMDMs upon B. abortus infection.…”

Section: Resultsmentioning

confidence: 99%

“…TLRs are transmembrane receptors, that recognize and bind pathogen‐associated molecular patterns (PAMPs), resulting in signal transduction and translocation of NF‐κB transcription factor to the nucleus and phosphorylation of mitogen‐ activated protein (MAP) kinases p38, JNK and ERK . Our laboratory and others have described the involvement of several TLRs and TLRs‐associated pathways, such as TLR9 and MyD88, in the recognition of B. abortus .…”

Section: Introductionmentioning

confidence: 99%

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NLRP12 negatively regulates proinflammatory cytokine production and host defense against Brucella abortus

et al. 2016

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Brucella abortus is the causative agent of brucellosis, which causes abortion in domestic animals and undulant fever in humans. This bacterium infects and proliferates mainly in macrophages and dendritic cells where is recognized by pattern recognition receptors (PRRs) including Nod-like receptors (NLRs). Our group recently demonstrated the role of AIM2 and NLRP3 in Brucella recognition. Here, we investigated the participation of NLRP12 in innate immune response to B. abortus. We found that NLRP12 inhibits the early production of IL-12 in bone marrow-derived macrophages upon B. abortus infection. We also observed that NLRP12 suppresses in vitro NF-κB and MAPK signaling in response to Brucella. Moreover, we showed that NLRP12 modulates caspase-1 activation and IL-1β secretion in B. abortus infected-macrophages. Furthermore, we observed that mice lacking NLRP12 were more resistant in the early stages of B. abortus infection. NLRP12−/− infected-mice presented reduced bacterial burdens in the spleens and increased production of IFN-γ and IL-1β compared to wild-type controls. In addition, NLRP12 deficiency leads to reduction in granuloma number and size in mouse livers. Altogether, our findings suggest that NLRP12 plays an important role in regulating negatively the early inflammatory responses against B. abortus.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NLRP12 negatively regulates proinflammatory cytokine production and host defense against Brucella abortus

et al. 2016

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“…It is clear that MyD88 is responding to Brucella infection of the joints, but the nature of the reacting cell types remains unknown. Numerous cell types in the joint, including macrophages, dendritic cells, synovial fibroblasts, chondrocytes, endothelial cells, and fibroblast-like synoviocytes, are capable of responding to exogenous and endogenous TLR ligands and could be mediating inflammation in our model (28,(54)(55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

“…This signaling can result in arthritis and osteoclastogenesis in murine models of bacterium-induced focal complications (25)(26)(27). Host cells reportedly recognize Brucella through TLR2, TLR4, TLR6, and TLR9 (28)(29)(30)(31)(32). To determine if MyD88 signaling is important for Brucella-induced arthritis, we investigated joint inflammatory responses in MyD88 Ϫ/Ϫ mice following footpad infection with Brucella.…”

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confidence: 99%

Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation

et al. 2017

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Brucella spp. are facultative intracellular Gram-negative bacteria that cause the zoonotic disease brucellosis, one of the most common global zoonoses. Osteomyelitis, arthritis, and musculoskeletal inflammation are common focal complications of brucellosis in humans; however, wild-type (WT) mice infected systemically with conventional doses of Brucella do not develop these complications. Here we report C57BL/6 WT mice infected via the footpad with 10 3 to 10 6 CFU of Brucella spp. display neutrophil and monocyte infiltration of the joint space and surrounding musculoskeletal tissue. Joint inflammation is detectable as early as 1 day postinfection and peaks 1 to 2 weeks later, after which WT mice are able to slowly resolve inflammation. B and T cells were dispensable for the onset of swelling but required for resolution of joint inflammation and infection. At early time points, MyD88 Ϫ/Ϫ mice display decreased joint inflammation, swelling, and proinflammatory cytokine levels relative to WT mice. Subsequently, swelling of MyD88 Ϫ/Ϫ joints surpassed WT joint swelling, and resolution of joint inflammation was prolonged. Joint bacterial loads in MyD88 Ϫ/Ϫ mice were significantly greater than those in WT mice by day 3 postinfection and at all time points thereafter. In addition, MyD88 Ϫ/Ϫ joint inflammatory cytokine levels on day 3 and beyond were similar to WT levels. Collectively these data demonstrate MyD88 signaling mediates early inflammatory responses in the joint but also contributes to subsequent clearance of Brucella and resolution of inflammation. This work also establishes a mouse model for studying Brucellainduced arthritis, musculoskeletal complications, and systemic responses, which will lead to a better understanding of focal complications of brucellosis.KEYWORDS arthritis, osteomyelitis, Brucella, brucellosis, MyD88, musculoskeletal B rucella spp. infect over 500,000 individuals each year, making brucellosis one of the most common global zoonoses (1). The most prevalent species that infect humans are Brucella melitensis, Brucella abortus, and Brucella suis (2). Transmission to humans typically occurs through the consumption of unpasteurized dairy products or via aerosol following contact with contaminated meat products (3, 4). Although vaccination of livestock has reduced disease incidence, no licensed human vaccine is available, and brucellosis has recently been designated a neglected zoonotic disease by the World Health Organization (5, 6). Osteoarticular and musculoskeletal inflammation are the most common focal complications of human brucellosis and occur in 40 to 80% of Brucella-infected patients (7,8). This arthritis is thought to arise from the hematogenous spread of Brucella to the joints, as viable brucellae can be found within the synovial fluid of infected patients (9, 10). Arthritis can manifest as peripheral arthritis, sacroiliitis, and spondylitis, which are most common in children, young adults and older adults, respectively (7,8,11,12). Inflammation of the joint synovium is pre...

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“…Furthermore, Gomes et al, 2015 [25] revealed that CpG motifs derived from Brucella DNA are involved in activation of host innate immune response through the TLR9 receptor. TLR9 plays an important role in initial control of infection by Brucella abortus [26].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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TLR9 is required for MAPK/NF-κB activation but does not cooperate with TLR2 or TLR6 to induce host resistance to Brucella abortus

Cited by 47 publications

References 44 publications

NLRP12 negatively regulates proinflammatory cytokine production and host defense against Brucella abortus

NLRP12 negatively regulates proinflammatory cytokine production and host defense against Brucella abortus

Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation

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

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