Enhanced LPS-induced peritonitis in mice deficiency of cullin 4B in macrophages

Mh, Hung; Yr, Jian; Cc, Tsao; Lin, Shi‐Ming; Chuang, Ya Hui

doi:10.1038/gene.2014.32

Cited by 16 publications

(12 citation statements)

References 37 publications

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“…Finally, the CRL4B complex was shown to regulate AKT-GSK3β activity by epigenetically repressing Pten transcription. However, our results differ from those of a report by Hung et al, 44 in which the authors showed that the deletion of CUL4B in macrophages enhanced LPS-induced peritonitis but not production of the proinflammatory cytokines IL-6 and TNF-α.…”

Section: Discussioncontrasting

confidence: 99%

CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription

Song

Qin

et al. 2019

Cell Mol Immunol

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Toll-like receptors (TLRs) play critical roles in innate immunity and inflammation. The molecular mechanisms by which TLR signaling is fine-tuned remain to be completely elucidated. Cullin 4B (CUL4B), which assembles the CUL4B-RING E3 ligase complex (CRL4B), has been shown to regulate diverse developmental and physiological processes by catalyzing monoubiquitination for histone modification or polyubiquitination for proteasomal degradation. Here, we identified the role of CUL4B as an intrinsic negative regulator of the TLR-triggered inflammatory response. Deletion of CUL4B in macrophages increased the production of proinflammatory cytokines and decreased anti-inflammatory cytokine IL-10 production in response to pathogens that activate TLR3, TLR4, or TLR2. Myeloid cell-specific Cul4b knockout mice were more susceptible to septic shock when challenged with lipopolysaccharide, polyinosinic-polycytidylic acid or Salmonella typhimurium infection. We further demonstrated that enhanced TLR-induced inflammatory responses in the absence of CUL4B were mediated by increased GSK3β activity. Suppression of GSK3β activity efficiently blocked the TLR-triggered increase in proinflammatory cytokine production and attenuated TLR-triggered death in Cul4b mutant mice. Mechanistically, CUL4B was found to negatively regulate TLR-triggered signaling by epigenetically repressing the transcription of Pten, thus maintaining the anti-inflammatory PI3K-AKT-GSK3β pathway. The upregulation of PTEN caused by CUL4B deletion led to uncontrolled GSK3β activity and excessive inflammatory immune responses. Thus, our findings indicate that CUL4B functions to restrict TLR-triggered inflammatory responses through regulating the AKT-GSK3β pathway.

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Section: Discussioncontrasting

confidence: 99%

CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription

Song

Qin

et al. 2019

Cell Mol Immunol

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“…This response includes phagocytosis of cellular debris and pathogens, secretion of cytokines, and stimulation of other immune cells. 25 Phagocytosis is one of the most efficient tools for the elimination of pathogens in acute infections, and serves as a marker for leukocyte function. 26 Bode and co-workers reported an increased in vitro phagocytic activity when LPS-stimulated monocytes were co-incubated with VAN.…”

Section: Discussionmentioning

confidence: 99%

Vancomycin and daptomycin modulate the innate immune response in a murine model of LPS-induced sepsis

Muenster

Zschernack

Dierig³

et al. 2021

Int J Immunopathol Pharmacol

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Sepsis is a leading cause of death worldwide, despite the use of multimodal therapies. Common antibiotic regimens are being affected by a rising number of multidrug-resistant pathogens, and new therapeutic approaches are therefore needed. Antibiotics have immunomodulatory properties which appear to be beneficial in the treatment of sepsis. We hypothesized that the last-resort antibiotics vancomycin (VAN) and daptomycin (DMC) modulate cell migration, phagocytosis, and protein cytokine levels in a murine model of lipopolysaccharide (LPS)-induced sepsis. Ten to twelve-week-old C57BL/6 mice ( n = 4–6 animals per group) were stimulated with LPS for 20 h, followed by the administration of VAN or DMC. The outcome parameters were leukocyte accumulation and effector function. Quantification of the immune cells in the peritoneal lavage was performed using flow cytometry analysis. Phagocytosis was measured using pHrodo E. coli BioParticles. The response of the cytokines TNFα, IL-6, and IL-10 was measured in vitro using murine peritoneal macrophages stimulated with LPS and VAN or DMC. VAN decreased both the peritoneal macrophage and the dendritic cell populations following LPS stimulation. DMC reduced the dendritic cell population in the peritoneal cavity in LPS-infected mice. Both antibiotics increased the phagocytic activity in peritoneal macrophages, but this effect was diminished in response to LPS. Phagocytosis of dendritic cells was increased in LPS-infected animals treated with VAN. VAN and DMC differently modulated the levels of pro-and anti-inflammatory cytokines. In a murine model of LPS-induced sepsis, VAN and DMC exhibit immunomodulatory effects on cells involved in innate immunity. The question of whether these antibiotics exhibit synergistic effects in the treatment of septic patients, beyond their bactericidal properties, should be further evaluated in future studies.

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“…Cul-5 haploinsufficiency improves survival and reduces proinflammatory cytokine production in response to LPS challenge A literature search of the Cul family proteins found publications suggesting that Cul-4a and Cul-4b contribute to immune cell functions (11)(12)(13). To investigate the potential functions of other Culs, such as Cul-5, in immune cells, we generated Cul-5-deficient mice using cryopreserved germplasm containing trapped Cul-5 alleles.…”

Section: Resultsmentioning

confidence: 99%

“…Together, these proteins form a Cul-RING domain ubiquitin ligase (CRL) that recruits ubiquitin E2s and catalyzes the ubiquitination of Cul substrates (9,10). In immune cells, Cul-4a is reported to affect the cell cycle and the differentiation of granulocytes (11), whereas Cul-4b maintains the mRNA level of TNF-a (12) and negatively regulates LPS signaling in macrophages (13). The biological functions of other Culs in the immune system remain largely unknown.…”

mentioning

confidence: 99%

Cutting Edge: A Cullin-5–TRAF6 Interaction Promotes TRAF6 Polyubiquitination and Lipopolysaccharide Signaling

Zhu

Wang

Hao

et al. 2016

The Journal of Immunology

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TNFR-associated factor (TRAF)6 integrates signals from multiple cell surface receptors for the activation of NF-κB. However, the mechanism underlying LPS-induced TRAF6 signaling remains unclear. We report that cullin-5 (Cul-5), a cullin family scaffold protein, binds to TRAF6 and promotes TRAF6 polyubiquitination at Lys63 in response to LPS stimulation. A direct interaction between the C-terminal domain of Cul-5 and the TRAF-C domain of TRAF6 facilitates polyubiquitination of TRAF6. Hemizygous Cul-5 knockout is associated with improved survival of mice following LPS challenge and significant delays in the phosphorylation of p65/RelA, ERK, JNK, and p38 MAPKs in LPS-stimulated macrophages, along with a marked decrease in NF-κB activation. These findings identify Cul-5 as a signaling component that connects an LPS-activated TLR4-MyD88 complex to TRAF6 for efficient activation of NF-κB.

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Enhanced LPS-induced peritonitis in mice deficiency of cullin 4B in macrophages

Cited by 16 publications

References 37 publications

CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription

CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription

Vancomycin and daptomycin modulate the innate immune response in a murine model of LPS-induced sepsis

Cutting Edge: A Cullin-5–TRAF6 Interaction Promotes TRAF6 Polyubiquitination and Lipopolysaccharide Signaling

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