Evidence of Brucella abortus OPS dictating uptake and restricting NF-κB activation in murine macrophages

Pei, Jianwu; Turse, Joshua E.; Ficht, Thomas A.

doi:10.1016/j.micinf.2008.01.005

Cited by 47 publications

(51 citation statements)

References 38 publications

(71 reference statements)

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“…Hence, we expected to determine the impact of the distinct signaling pathways associated with TLR4/JAK2 on phagocytic mechanisms of Brucella. Some studies have revealed that TLR4 is important for Brucella uptake and cellular responses in macrophages (14,24). In this study, we showed that the internalization of B. abortus is strongly suppressed by the disruption of TLR4.…”

Section: Discussionsupporting

confidence: 50%

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Toll-Like Receptor 4-Linked Janus Kinase 2 Signaling Contributes to Internalization of Brucella abortus by Macrophages

Lee

Kim

et al. 2013

Infect Immun

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e Brucella abortus is an intracellular pathogen that uses a crafty strategy to invade and proliferate within host cells, but the distinct signaling pathways associated with phagocytic mechanisms of B. abortus remain unclear. The present study was performed to test the hypothesis that Toll-like receptor 4 (TLR4)-linked signaling interacting with Janus kinase 2 (JAK2) plays an essential role in B. abortus phagocytosis by macrophages. The effects of TLR4-JAK2 signaling on B. abortus phagocytosis in murine macrophage RAW 264.7 cells were observed through an infection assay and confocal microscopy. We determined that the uptake of B. abortus was negatively affected by the dysfunction of TLR4 and JAK2. F-actin polymerization detected by flow cytometry and F-actin assay was amplified for B. abortus entry, whereas that event was attenuated by the disruption of TLR4 and JAK2. Importantly, JAK2 phosphorylation and actin skeleton reorganization were suppressed immediately after B. abortus infection in bone marrow-derived macrophages (BMDMs) from TLR4 ؊/؊ mice, showing the cooperation of JAK2 with TLR4. Furthermore, small GTPase Cdc42 participated in the intermediate pathway of TLR4-JAK2 signaling on B. abortus phagocytosis. Consequently, TLR4-associated JAK2 activation in the early cellular signaling events plays a pivotal role in B. abortus-induced phagocytic processes in macrophages, implying the pathogenic significance of JAK2-mediated entry. Here, we elucidate that this specific phagocytic mechanism of B. abortus might provide achievable strategies for inhibiting B. abortus invasion.

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Section: Discussionsupporting

confidence: 50%

“…Ligation of TLR4 promotes the activation of complex signaling pathways, including mitogen-acti-functions, including phagocytosis (23). Nevertheless, the downstream signaling cascades subsequent to the entry of B. abortus into epithelial cells (3,9) and murine macrophages (24) have not been fully elucidated.…”

mentioning

confidence: 99%

Toll-Like Receptor 4-Linked Janus Kinase 2 Signaling Contributes to Internalization of Brucella abortus by Macrophages

Lee

Kim

et al. 2013

Infect Immun

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“…1) (7), another way to compare macrophage responses to rough and smooth brucellae is to use differential MOIs (roughly 10-fold difference) for the initial infection to achieve the same Brucella cells taken up by macrophages. However, this method ignores the potential influence of extracellular brucellae on the macrophage responses (e.g., Toll-like receptor 4 [TLR4] activation) (31). Those brucellae outside macrophages may interact with the macrophage cell surface proteins or other factors and trigger active macrophage responses.…”

Section: Resultsmentioning

confidence: 99%

Proinflammatory Caspase-2-Mediated Macrophage Cell Death Induced by a Rough Attenuated Brucella suis Strain

Chen

Ding

et al. 2011

Infect Immun

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Brucella spp. are intracellular bacteria that cause an infectious disease called brucellosis in humans and many domestic and wildlife animals. B. suis primarily infects pigs and is pathogenic to humans. The macrophage-Brucella interaction is critical for the establishment of a chronic Brucella infection. Our studies showed that smooth virulent B. suis strain 1330 (S1330) prevented programmed cell death of infected macrophages and rough attenuated B. suis strain VTRS1 (a vaccine candidate) induced strong macrophage cell death. To further investigate the mechanism of VTRS1-induced macrophage cell death, microarrays were used to analyze temporal transcriptional responses of murine macrophage-like J774.A1 cells infected with S1330 or VTRS1. In total 17,685 probe sets were significantly regulated based on the effects of strain, time and their interactions. A miniTUBA dynamic Bayesian network analysis predicted that VTRS1-induced macrophage cell death was mediated by a proinflammatory gene (the tumor necrosis factor alpha [TNF-␣] gene), an NF-B pathway gene (the IB-␣ gene), the caspase-2 gene, and several other genes. VTRS1 induced significantly higher levels of transcription of 40 proinflammatory genes than S1330. A Mann-Whitney U test confirmed the proinflammatory response in VTRS1-infected macrophages. Increased production of TNF-␣ and interleukin 1␤ (IL-1␤) were also detected in the supernatants in VTRS1-infected macrophage cell culture. Hyperphosphorylation of IB-␣ was observed in macrophages infected with VTRS1 but not S1330. The important roles of TNF-␣ and IB-␣ in VTRS1-induced macrophage cell death were further confirmed by individual inhibition studies. VTRS1-induced macrophage cell death was significantly inhibited by a caspase-2 inhibitor but not a caspase-1 inhibitor. The role of caspase-2 in regulating the programmed cell death of VTRS1-infected macrophages was confirmed in another study using caspase-2-knockout mice. In summary, VTRS1 induces a proinflammatory, caspase-2-and NF-B-mediated macrophage cell death. This unique cell death differs from apoptosis, which is not proinflammatory. It is also different from classical pyroptosis, which is caspase-1 mediated.Brucella spp. are facultative, intracellular, Gram-negative bacteria that cause a zoonotic disease called brucellosis in swine, cattle, other animals, and humans. Human brucellosis remains the most common zoonotic disease worldwide, with more than 500,000 new cases reported annually (28). B. suis is the main causative agent of brucellosis in swine and humans (28). Brucella enters and replicates efficiently in a variety of cells, including macrophages, epithelial cells, dendritic cells, and trophoblasts (34). Interaction between Brucella and macrophages is critical for the establishment of a chronic infection. The virulence of Brucella relies on its ability to survive and replicate in the vacuolar compartments of macrophages (18). In contrast, many rough derivatives of B. suis, B. abortus, and B. melitensis, which are deficient in the O antigen (o...

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“…88 Moreover, the replication of B. abortus S19 strain and S2308 strain in vivo has also been demonstrated to be TLR4-independent. 89 Interestingly, Pei et al 90 have demonstrated that TLR4 is involved in the internalization of smooth B. abortus in macrophages. 90 Of note, a recent study using unlipidated outer membrane protein 16 of B. abortus indicated that the production of pro-inflammatory cytokines induced by this unlipidated protein is TLR4-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…89 Interestingly, Pei et al 90 have demonstrated that TLR4 is involved in the internalization of smooth B. abortus in macrophages. 90 Of note, a recent study using unlipidated outer membrane protein 16 of B. abortus indicated that the production of pro-inflammatory cytokines induced by this unlipidated protein is TLR4-dependent. 80 In our study, high levels of antigen-specific Th1-type cytokines such as IFN-c and IL-2 and high levels of protection against B. abortus infection were observed in wild-type mice vaccinated with the rBCSP31 vaccine compared with these parameters in TLR2 2/2 and TLR4 2/2 mice.…”

Section: Discussionmentioning

confidence: 99%

TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

Yuan

Gao

et al. 2014

Cell Mol Immunol

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Brucella abortus is a zoonotic Gram-negative pathogen that causes brucelosis in ruminants and humans. Toll-like receptors (TLRs) recognize Brucella abortus and initiate antigen-presenting cell activities that affect both innate and adaptive immunity. In this study, we focused on recombinant Brucella cell-surface protein 31 (rBCSP31) to determine its effects on mouse macrophages. Our results demonstrated that rBCSP31 induced TNF-a, IL-6 and IL-12p40 production, which depended on the activation of mitogen-activated protein kinases (MAPKs) by stimulating the rapid phosphorylation of p38 and JNK and the activation of transcription factor NF-kB in macrophages. In addition, continuous exposure (.24 h) of RAW264.7 cells to rBCSP31 significantly enhanced IFN-c-induced expression of MHC-II and the ability to present rBCSP31 peptide to CD4 1 T cells. Furthermore, we found that rBCSP31 could interact with both TLR2 and TLR4. The rBCSP31-induced cytokine production by macrophages from TLR2 2/2 and TLR4 2/2 mice was lower than that from C57BL/6 macrophages, and the activation of NF-kB and MAPKs was attenuated in macrophages from TLR2 2/2 and TLR4 2/2 mice. In addition, CD4 1 T cells from C57BL/6 mice immunized with rBCSP31 produced higher levels of IFN-c and IL-2 compared with CD4 1 T cells from TLR2 2/2 and TLR4 2/2 mice. Macrophages from immunized C57BL/6 mice produced higher levels of IL-12p40 than those from TLR2 2/2 and TLR4 2/2 mice. Furthermore, immunization with rBCSP31 provided better protection in C57BL/6 mice than in TLR2 2/2 and TLR4 2/2 mice after B. abortus 2308 challenge. These results indicate that rBCSP31 is a TLR2 and TLR4 agonist that induces cytokine production, upregulates macrophage function and induces the Th1 immune response.

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Evidence of Brucella abortus OPS dictating uptake and restricting NF-κB activation in murine macrophages

Cited by 47 publications

References 38 publications

Toll-Like Receptor 4-Linked Janus Kinase 2 Signaling Contributes to Internalization of Brucella abortus by Macrophages

Toll-Like Receptor 4-Linked Janus Kinase 2 Signaling Contributes to Internalization of Brucella abortus by Macrophages

Proinflammatory Caspase-2-Mediated Macrophage Cell Death Induced by a Rough Attenuated Brucella suis Strain

TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

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