CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3

Paudel, Sagar; Baral, Pankaj; Ghimire, Laxman; Bergeron, Scott; Jin, Liliang; DeCorte, Joseph A.; Le, John; Cai, Shanshan; Jeyaseelan, Samithamby

doi:10.1182/blood-2018-10-878082

Cited by 89 publications

(76 citation statements)

References 49 publications

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“…Sepsis is caused by an overshooting answer of the immune system on the infection, resulting in injuring its own organs. This acute pro-inflammatory response of the body is mainly driven by polymorphonuclear neutrophils (PMNs) as the first cells of the immune system to be recruited to the side of inflammation (7,8). Accordingly, PMNs are considered as a prognostic marker for mortality in terms of sepsis (9) as they migrate from the circulatory system into the inflamed tissue.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CXCR4 and CXCR7 Is Protective in Acute Peritoneal Inflammation

et al. 2020

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Our previous studies revealed a pivotal role of the chemokine stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 on migratory behavior of polymorphonuclear granulocytes (PMNs) in pulmonary inflammation. Thereby, the SDF-1-CXCR4/CXCR7-axis was linked with adenosine signaling. However, the role of the SDF-1 receptors CXCR4 and CXCR7 in acute inflammatory peritonitis and peritonitis-related sepsis still remained unknown. The presented study provides new insight on the mechanism of a selective inhibition of CXCR4 (AMD3100) and CXCR7 (CCX771) in two models of peritonitis and peritonitis-related sepsis by injection of zymosan and fecal solution. We observed an increased expression of SDF-1, CXCR4, and CXCR7 in peritoneal tissue and various organs during acute inflammatory peritonitis. Selective inhibition of CXCR4 and CXCR7 reduced PMN accumulation in the peritoneal fluid and infiltration of neutrophils in lung and liver tissue in both models. Both inhibitors had no anti-inflammatory effects in A 2B knockout animals (A 2B-/-). AMD3100 and CCX771 treatment reduced capillary leakage and increased formation of tight junctions as a marker for microvascular permeability in wild type animals. In contrast, both inhibitors failed to improve capillary leakage in A 2B-/-animals, highlighting the impact of the A 2B-receptor in SDF-1 mediated signaling. After inflammation, the CXCR4 and CXCR7 antagonist induced an enhanced expression of the protective A 2B adenosine receptor and an increased activation of cAMP (cyclic adenosine mono phosphate) response element-binding protein (CREB), as downstream signaling pathway of A 2B. The CXCR4-and CXCR7-inhibitor reduced the release of cytokines in wild type animals via decreased intracellular phosphorylation of ERK and NFκB p65. In vitro, CXCR4 and CXCR7 antagonism diminished the chemokine release of human cells and increased cellular integrity by enhancing the expression of tight junctions. These protective effects were linked with functional A 2B-receptor signaling, confirming our in vivo data. In conclusion, our study revealed new protective aspects of the pharmacological modulation of the SDF-1-CXCR4/CXCR7-axis during acute peritoneal inflammation in terms of the two hallmarks PMN migration and barrier integrity. Both anti-inflammatory effects were linked with functional adenosine A 2B-receptor signaling.

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Section: Introductionmentioning

confidence: 99%

Inhibition of CXCR4 and CXCR7 Is Protective in Acute Peritoneal Inflammation

et al. 2020

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“…In OF-induced equine laminitis, increased gene expression of CXCL-1 and MCP-2 and the migration of neutrophils and mononuclear cells into lamellae are observed (20). A recent study reported that CXCL-1 could induce neutrophils to infiltrate the sites of bacterial infection and was involved in the granulopoiesis and mobilization of neutrophils in sepsis (56). Furthermore, MCP-2 is another important chemokine in inflammation and immunomodulation, which could activate mononuclear cells and direct them into target tissues (57).…”

Section: Discussionmentioning

confidence: 99%

Laminar Inflammation Responses in the Oligofructose Overload Induced Model of Bovine Laminitis

Ding

Jiang

et al. 2020

Front. Vet. Sci.

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Bovine laminitis causes substantial economic losses and animal welfare problems in dairy farms worldwide. Previously published studies have reported that the inflammatory response plays a central role in the pathogenesis of the disease. To our knowledge, inflammation associated with bovine laminitis induced by high levels of exposure to oligofructose (OF) has not been reported and characterized. In fact, the disease manifestations in this model closely approximate those of clinical laminitis. The objective of this study was to characterize the inflammatory response in OF-induced bovine laminitis. A total of 12 Chinese Holstein dairy heifers were utilized in this study. The heifers were randomly divided into two groups, treatment (n = 6) and control (n = 6). The treatment group heifers were administered OF solutions via a stomach tube (dose: 17 g/kg of body weight). Upon development of a lameness score of 2 with consecutive positive reactions in the same claw, they would be humanely euthanized. Control heifers were administered deionized water (dose: 2 L/100 kg of body weight) and humanely euthanized at 72 h. Real-time quantitative PCR (qPCR) assays were performed to determine the messenger RNA (mRNA) concentrations of inflammatory mediators in the lamellae. Concentrations of interleukin (IL)-1β, IL-6, IL-8, C-X-C motif chemokine ligand-1 (CXCL-1), macrophage cationic peptide-2 (MCP-2), E-selectin, intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase-1 (iNOS-1), and plasminogen activator inhibitor-1 (PAI-1) were significantly increased (P < 0.05) in the treatment group. No significant difference was found for tumor necrosis factor alpha (TNF-α), IL-10, CXCL-6, and MCP-1. These results demonstrated and characterized the laminar inflammatory response leading to the pathogenesis of bovine laminitis at the early stages.

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“…Our current study elucidates a regulatory mechanism mediated by the miR-127/A20/STAT3 axis, which plays a key role in modulating macrophage anti-bacterial responses. However, as STAT3-driven anti-microbial signaling is also triggered by other immune cell subsets such as innate lymphoid cells and gd T cells (Baral et al, 2018;Xiong et al, 2016;Paudel et al, 2019), we currently cannot exclude the effect of miR-127 on these cells' response to bacterial infection, the topic of which is currently under investigation in our lab.…”

Section: Limitations Of the Studymentioning

confidence: 99%

MicroRNA-127 Promotes Anti-microbial Host Defense through Restricting A20-Mediated De-ubiquitination of STAT3

Liu¹,

Mao²,

Kang³

et al. 2020

iScience

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The increasing rising of multiple drug-resistant Staphylococcus aureus has become a major public health concern, underscoring a pressing need for developing therapies essentially based on the understanding of host defensive mechanism. In the present study, we showed that microRNA (miR)-127 played a key role in controlling bacterial infection and conferred a profound protection against staphylococcal pneumonia. The protective effect of miR-127 was largely dependent on its regulation of macrophage bactericidal activity and the generation of IL-22, IL-17, and anti-microbial peptides (AMPs), the pathway primarily driven by STAT3. Importantly, we revealed that the ubiquitin-editing enzyme A20, a genuine target of miR-127, specifically interacted with and repressed K63-ubiquitination of STAT3, thereby compromising its phosphorylation upon bacterial infection. Thus, our data not only identify miR-127 as a non-coding molecule with anti-bacterial activity but also delineate an unappreciated mechanism whereby A20 regulates STAT3-driven anti-microbial signaling via modulating its ubiquitination.

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CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3

Cited by 89 publications

References 49 publications

Inhibition of CXCR4 and CXCR7 Is Protective in Acute Peritoneal Inflammation

Inhibition of CXCR4 and CXCR7 Is Protective in Acute Peritoneal Inflammation

Laminar Inflammation Responses in the Oligofructose Overload Induced Model of Bovine Laminitis

MicroRNA-127 Promotes Anti-microbial Host Defense through Restricting A20-Mediated De-ubiquitination of STAT3

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