Suppressors of cytokine signaling 3 is essential for FcγR-mediated inflammatory response via enhancing CCAAT/enhancer-binding protein δ transcriptional activity in macrophages

Yan, Chunguang; Liu, Yanlan; Gao, Hongwei; Wang, Ximo

doi:10.1016/j.yexcr.2015.07.017

Cited by 9 publications

(4 citation statements)

References 33 publications

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“…Sixteen-week-old male myeloid-specific SOCS-3-knockout (SOCS-3-KO) C57Bl6-B.129 mice and C57Bl6-B.129 wild-type (WT) mice were engineered as previously described (Yan et al 2015). Mice were genotyped by real-time polymerase chain reaction (Transnetyx).…”

Section: Methodsmentioning

confidence: 99%

SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis

Papathanasiou

Kantarcı²,

Konstantinidis

et al. 2016

J Dent Res

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The host immune response plays a key role in bacteria-induced alveolar bone resorption. Endogenous control of the magnitude and duration of inflammatory signaling is considered an important determinant of the extent of periodontal pathology. Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling pathways and may play a role in restraining periodontal inflammation. We hypothesized that SOCS-3 regulates alveolar bone loss in experimental periodontitis. Periodontal bone loss was induced in 16-wkold myeloid-specific SOCS-3-knockout and wild-type (WT) C57Bl6-B.129 mice by oral inoculation 9 times with 10 9 colony-forming units of Porphyromonas gingivalis A7436 through an oral gavage model for periodontitis. Sham controls for both types of mice received vehicle without bacteria. The mice were euthanized 6 wk after the last oral inoculation. Increased bone loss was demonstrated in P. gingivalis-infected SOCS-3-knockout mice as compared with P. gingivalis-infected WT mice by direct morphologic measurements, micro-computed tomography analyses, and quantitative histology. Loss of SOCS-3 function resulted in an increased number of alveolar bone osteoclasts and increased RANKL expression after P. gingivalis infection. SOCS-3 deficiency in myeloid cells also promotes a higher P. gingivalis lipopolysaccharide-induced inflammatory response with higher secretion of IL-1β, IL-6, and KC (IL-8) by peritoneal macrophages as compared with WT controls. Our data implicate SOCS-3 as a critical negative regulator of alveolar bone loss in periodontitis.

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Section: Methodsmentioning

confidence: 99%

SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis

Papathanasiou

Kantarcı²,

Konstantinidis

et al. 2016

J Dent Res

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“…Genes induced by STAT6 were down-regulated compared with uninfected Stat1 À/À mice. Expression levels of immune response genes induced by STAT3, Lrg1, associated with neutrophil function, 54 and Cebpd, a transcription factor associated with suppressor of cytokine signaling 3 signaling in macrophages, 55 were increased in infected Stat1 À/À mice but were not changed or not detected in infected WT mice. In addition, the IBD biomarker Fcgr1, 56 the high-affinity receptor for the Fc portion of Ig g receptor (alias Cd64), which is linked to both STAT4 and STAT3 signaling, 57 was up-regulated in infected Stat1 À/À mice.…”

Section: Mnv-4 Infection Increases Expression Levels Of Target Genes mentioning

confidence: 99%

Obstructive Lymphangitis Precedes Colitis in Murine Norovirus–Infected Stat1-Deficient Mice

Seamons

Treuting

Meeker

et al. 2018

The American Journal of Pathology

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Murine norovirus (MNV) is an RNA virus that can prove lethal in mice with impaired innate immunity. We found that MNV-4 infection of Stat1 mice was not lethal, but produced a 100% penetrant, previously undescribed lymphatic phenotype characterized by chronic-active lymphangitis with hepatitis, splenitis, and chronic cecal and colonic inflammation. Lesion pathogenesis progressed from early ileal enteritis and regional dilated lymphatics to lymphangitis, granulomatous changes in the liver and spleen, and, ultimately, typhlocolitis. Lesion development was neither affected by antibiotics nor reproduced by infection with another enteric RNA virus, rotavirus. MNV-4 infection in Stat1 mice decreased expression of vascular endothelial growth factor (Vegf) receptor 3, Vegf-c, and Vegf-d and increased interferon (Ifn)-γ, tumor necrosis factor-α, and inducible nitric oxide synthase. However, anti-IFN-γ and anti-tumor necrosis factor-α antibody treatment did not attenuate the histologic lesions. Studies in Ifnαβγr mice suggested that canonical signaling via interferon receptors did not cause MNV-4-induced disease. Infected Stat1 mice had increased STAT3 phosphorylation and expressed many STAT3-regulated genes, consistent with our findings of increased myeloid cell subsets and serum granulocyte colony-stimulating factor, which are also associated with increased STAT3 activity. In conclusion, in Stat1 mice, MNV-4 induces lymphatic lesions similar to those seen in Crohn disease as well as hepatitis, splenitis, and typhlocolitis. MNV-4-infected Stat1 mice may be a useful model to study mechanistic associations between viral infections, lymphatic dysfunction, and intestinal inflammation in a genetically susceptible host.

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“…According to the current paradigm, C/EBPδ acts as a pro-inflammatory transcription factor enhancing the expression of pro-inflammatory mediators [ 4 , 5 ]. Indeed, C/EBPδ is shown to regulate IL-1β or collagen-induced cyclo-oxygenase-2 (COX-2) expression [ 6 , 7 , 8 ]; to induce toll-like receptor (TLR)-4 expression and subsequent signalling [ 9 ]; to potentiate Fcγ receptor-mediated tumor necrosis factor alpha (TNFα), macrophage inflammatory protein (MIP)-2 and MIP-1α expression [ 10 ]; to mediate IgG immune complex-induced macrophages inflammatory cytokine and chemokine production in macrophages [ 11 , 12 ]; and to enhance lipopolysaccharide (LPS)-induced IL-6, monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 levels [ 13 ]. In line with its proinflammatory role in vitro, C/EBPδ also seems to play an important role in the inflammatory response in vivo.…”

Section: Introductionmentioning

confidence: 99%

CEBPD Potentiates the Macrophage Inflammatory Response but CEBPD Knock-Out Macrophages Fail to Identify CEBPD-Dependent Pro-Inflammatory Transcriptional Programs

Spek

Aberson

Butler

et al. 2021

Cells

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CCAAT/enhancer-binding protein delta (C/EBPδ) is a member of the C/EBP family of transcription factors. According to the current paradigm, C/EBPδ potentiates cytokine production and modulates macrophage function thereby enhancing the inflammatory response. Remarkably, however, C/EBPδ deficiency does not consistently lead to a reduction in Lipopolysaccharide (LPS)-induced cytokine production by macrophages. Here, we address this apparent discrepancy and show that the effect of C/EBPδ on cytokine production and macrophage function depends on both the macrophage subtype and the LPS concentration used. Using CRISPR-Cas generated macrophages in which the transactivation domain of C/EBPδ was deleted from the endogenous locus (ΔTAD macrophages), we next show that the context-dependent role of C/EBPδ in macrophage biology relies on compensatory transcriptional activity in the absence of C/EBPδ. We extend these findings by revealing a large discrepancy between transcriptional programs in C/EBPδ knock-out and C/EBPδ transactivation dead (ΔTAD) macrophages implying that compensatory mechanisms do not specifically modify C/EBPδ-dependent inflammatory responses but affect overall macrophage biology. Overall, these data imply that knock-out approaches are not suited for identifying the genuine transcriptional program regulated by C/EBPδ, and we suggest that this phenomenon applies for transcription factor families in general.

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Suppressors of cytokine signaling 3 is essential for FcγR-mediated inflammatory response via enhancing CCAAT/enhancer-binding protein δ transcriptional activity in macrophages

Cited by 9 publications

References 33 publications

SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis

SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis

Obstructive Lymphangitis Precedes Colitis in Murine Norovirus–Infected Stat1-Deficient Mice

CEBPD Potentiates the Macrophage Inflammatory Response but CEBPD Knock-Out Macrophages Fail to Identify CEBPD-Dependent Pro-Inflammatory Transcriptional Programs

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