Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis

Alazawi, William; Heath, H; Waters, Jennifer A.; Woodfin, Abigail; O’Brien, Alastair; Scarzello, Anthony J.; Ma, Bin; Lopez-Otalora, Yolanda; Jacobs, Michael; Petts, Gemma; Goldin, Robert; Nourshargh, Sussan; Gamero, Ana M.; Foster, Graham R.

doi:10.1073/pnas.1221652110

Cited by 36 publications

(40 citation statements)

References 41 publications

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“…Compared with WT mice, however, we demonstrated that Park7 −/− mice are more susceptible to LPS-induced sepsis accompanied by impaired cytokine and chemokine production. Interestingly, similar phenomenon was also observed by Foster's group in Stat2 −/− mice [41]. These findings strongly suggest the existence of an alternative, cytokine storm-independent mechanism of LPS-induced septic death.…”

Section: Discussionsupporting

confidence: 87%

Park7 interacts with p47phox to direct NADPH oxidase-dependent ROS production and protect against sepsis

Liu

Chen

et al. 2015

Cell Res

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Inappropriate inflammation responses contribute to mortality during sepsis. Through Toll-like receptors (TLRs), reactive oxygen species (ROS) produced by NADPH oxidase could modulate the inflammation responses. Parkinson disease (autosomal recessive, early onset) 7 (Park7) has a cytoprotective role by eliminating ROS. However, whether Park7 could modulate inflammation responses and mortality in sepsis is unclear. Here, we show that, compared with wild-type mice, Park7 −/− mice had significantly increased mortality and bacterial burdens in sepsis model along with markedly decreased systemic and local inflammation, and drastically impaired macrophage phagocytosis and bacterial killing abilities. Surprisingly, LPS and phorbol-12-myristate-13-acetate stimulation failed to induce ROS and proinflammatory cytokine production in Park7 −/− macrophages and Park7-deficient RAW264.7 cells. Through its C-terminus, Park7 binds to p47 phox , a subunit of the NADPH oxidase, to promote NADPH oxidase-dependent production of ROS. Restoration of Park7 expression rescues ROS production and improves survival in LPS-induced sepsis. Together, our study shows that Park7 has a protective role against sepsis by controlling macrophage activation, NA-DPH oxidase activation and inflammation responses.

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Section: Discussionsupporting

confidence: 87%

Park7 interacts with p47phox to direct NADPH oxidase-dependent ROS production and protect against sepsis

Liu

Chen

et al. 2015

Cell Res

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“…An MPO assay was performed in the peritoneal fluid as described elsewhere (2,5,11,12). Briefly, 200 μl of peritoneal fluid was incubated with 800 μl hexadecyltrimethylammoniumbromide (HTAB) buffer and the mixture was transferred into microcentrifuge tube and centrifuged at 20,000 × g for 4 min.…”

Section: Methodsmentioning

confidence: 99%

“…CXCL1 controls neutrophil recruitment (one arm) and neutrophil function (other arm). In one arm, CXCL1 activates NF-κB, MAPK (3) and upregulation of cell adhesion molecules (ICAM-1) along with the production of cytokines/chemokines (4) in order to induce neutrophil recruitment to the tissues from the bloodstream (5). In the second arm, CXCL1 regulates the production of IL-17 (IL-17A) (6) resulting in the production of CXCL2/MIP-2 and IL-6 (7) in order to induce neutrophil recruitment (8).…”

Section: Figurementioning

confidence: 99%

“…Prior studies have shown that deletion of nucleotide-binding oligomerization domain-2 (NOD2) receptors or the scavenger receptor class A leads to host protection (3, 4). In contrast, reduced survival and diminished production of cytokines and chemokineswas observed in Stat-2 −/− mice during lipopolysaccharide (LPS)-mediated endotoxic shock, indicating a crucial role for STAT-2 in host defense (5). …”

Section: Introductionmentioning

confidence: 99%

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CXCL1 Contributes to Host Defense in Polymicrobial Sepsis via Modulating T Cell and Neutrophil Functions

Jin

Batra

Douda

et al. 2014

The Journal of Immunology

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Severe bacterial sepsis leads to a pro-inflammatory condition that can manifest as septic shock, multiple organ failure, and death. Neutrophils are critical for the rapid elimination of bacteria, however, the role of neutrophil chemoattractant CXCL1 in bacterial clearance during sepsis remains elusive. To test the hypothesis that CXCL1 is critical to host defense during sepsis. We used CXCL1-deficient mice and bone marrow chimeras to demonstrate the importance of this molecule in sepsis. We demonstrate that CXCL1 plays a pivotal role in mediating host defense to polymicrobial sepsis following cecal ligation and puncture (CLP) in gene-deficient mice. CXCL1 appears to be essential for restricting bacterial outgrowth and death in mice. CXCL1 derived from both hematopoietic and resident cells contributed to bacterial clearance. Moreover, CXCL1 is essential for neutrophil migration, expression of pro-inflammatory mediators, activation of Nuclear-Factor-κ-B (NF-κB) and Mitogen-Activated Protein (MAP) kinases and upregulation of adhesion molecule Intercellular Adhesion Molecule-1 (ICAM-1). Recombinant interleukin 17 (IL-17) rescued impaired host defenses in cxcl1−/− mice. CXCL1 is important for IL-17A production via Th17 differentiation. CXCL1 is essential for Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase-mediated reactive oxygen species production and neutrophil extracellular trap (NET) formation. This study reveals a novel role for CXCL1 in neutrophil recruitment via modulating T cell function and neutrophil-related bactericidal functions. These studies suggest that modulation of CXCL1 levels in tissues and blood could reduce bacterial burden in sepsis.

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“…The phosphorylation of STAT2 and not STAT3 is indicative of activation of specific intracellular pathways. STAT2 is a critical component of type I IFN signalling, but is not thought to participate in TLR associated signalling (Alazawi et al, 2013). STAT2 signalling is induced predominantly by type I and type III IFN receptors suggesting that activation of STAT2 in our studies is due to autocrine IFN signalling.…”

Section: Discussionmentioning

confidence: 61%

Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus

Roberts

Hill

Davis

et al. 2015

Journal of General Virology

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Rift Valley fever virus (RVFV) is the most pathogenic member of the genus Phlebovirus within the family Bunyaviridae, and can cause severe disease in humans and livestock. Until recently, limited information has been published on the cellular host response elicited by RVFV, particularly in macrophages and dendritic cells, which play critical roles in stimulating adaptive and innate immune responses to viral infection. In an effort to define the initial response of host immunomodulatory cells to infection, primary mouse bone marrow derived macrophages (BMDM) were infected with the pathogenic RVFV strain ZH501, or attenuated strains MP-12 or MP-12 based Clone13 type (rMP12-C13 type), and cytokine secretion profiles examined. The secretion of T helper (Th)1-associated antiviral cytokines, chemokines and various interleukins increased rapidly after infection with the attenuated rMP12-C13 type RVFV, which lacks a functional NSs virulence gene. In comparison, infection with live-attenuated MP-12 encoding a functional NSs gene appeared to cause a delayed immune response, while pathogenic ZH501 ablates the immune response almost entirely. These data demonstrate that NSs can inhibit components of the BMDM antiviral response and supports previous work indicating that NSs can specifically regulate the type I interferon response in macrophages. Furthermore, our data demonstrate that genetic differences between ZH501 and MP-12 reduce the ability of MP-12 to inhibit antiviral signalling and subsequently reduce virulence in BMDM, demonstrating that viral components other than NSs play a critical role in regulating the host response to RVFV infection.

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Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis

Cited by 36 publications

References 41 publications

Park7 interacts with p47phox to direct NADPH oxidase-dependent ROS production and protect against sepsis

Park7 interacts with p47phox to direct NADPH oxidase-dependent ROS production and protect against sepsis

CXCL1 Contributes to Host Defense in Polymicrobial Sepsis via Modulating T Cell and Neutrophil Functions

Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus

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