RAGE Deficiency Impairs Bacterial Clearance in Murine Staphylococcal Sepsis, but Has No Significant Impact on Staphylococcal Septic Arthritis

Mohammad, Majd; Na, Manli; Welin, Amanda; Svensson, Mattias; Ali, Abukar; Jin, Tao; Pullerits, Rille

doi:10.1371/journal.pone.0167287

Cited by 9 publications

(8 citation statements)

References 40 publications

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“…26 RAGE deficiency impairs clearance of Staphylococcus aureus in sepsis in mice. 27 In addition, RAGE activation alters inflammation and bacterial clearance in a murine model of pneumonia caused by Acinetobacter baumannii . 28 In this study, we showed that H. parasuis activated expression of RAGE in PAVECs and baicalin reduced RAGE expression, but the mechanism of action of RAGE resulting in inflammation, and further study is needed to determine how baicalin reduces RAGE expression.…”

Section: Discussionmentioning

confidence: 99%

Baicalin modulates apoptosis via RAGE, MAPK, and AP-1 in vascular endothelial cells during Haemophilus parasuis invasion

Zhao

Xiong

et al. 2019

Innate Immun

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Glässer’s disease, caused by Haemophilus parasuis, is a chronic disease related to an inflammatory immune response. Baicalin exerts important biological functions. In this study, we explored the protective efficacy of treatment with baicalin and the potential mechanism of activation of the MAPK signaling pathway in porcine aortic vascular endothelial cells (PAVECs) induced by H. parasuis. H. parasuis stimulated expression of receptor for advanced glycation end products, induced a significant increase in the level of protein kinase-α and protein kinase-δ phosphorylation, and significantly up-regulated ERK, c-Jun N-terminal kinase, and p38 phosphorylation in PAVECs. H. parasuis also up-regulated the levels of apoptotic genes ( Bax, C-myc, and Fasl) and the expression levels of c-Jun and c-Fos, and induced S-phase arrest in PAVECs. However, treatment with baicalin inhibited expression of RAGE, suppressed H. parasuis-induced protein kinase-α and protein kinase-δ phosphorylation, reduced ERK, c-Jun N-terminal kinase, and p38 phosphorylation, down-regulated apoptotic genes ( Bax, C-myc, and Fasl), attenuated phospho-c-Jun production from the extracellular to the nuclei, and reversed S-phase arrest in PAVECs. In conclusion, baicalin treatment inhibited the MAPK signaling pathway, thereby achieving its anti-inflammatory responses, which provides a new strategy to control H. parasuis infection.

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Section: Discussionmentioning

confidence: 99%

Baicalin modulates apoptosis via RAGE, MAPK, and AP-1 in vascular endothelial cells during Haemophilus parasuis invasion

Zhao

Xiong

et al. 2019

Innate Immun

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“…The animals were sacrificed if deemed not to survive until the next scheduled time point and considered dead. All mice were euthanized on day 10 post-infection, and serum samples, kidneys, and the paws were collected and stored as previously described 9 . The results from those three independent experiments displayed a similar pattern and the data were pooled.…”

Section: Methodsmentioning

confidence: 99%

“…Arthritis was defined as erythema and/or swelling of the joints. A clinical scoring system ranging from 0 to 3 points was used for each paw, as described before 9,34 . The arthritis index was constructed by adding the scores from all 4 limbs of each mouse, whereby each animal could be awarded a maximum of 12.…”

Section: Methodsmentioning

confidence: 99%

The role of Staphylococcus aureus lipoproteins in hematogenous septic arthritis

Mohammad

Ali

et al. 2020

Sci Rep

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permanent joint dysfunction is a devastating complication in patients with septic arthritis. Staphylococcus aureus (S. aureus) lipoproteins (Lpp), the predominant ligands for TLR2, are known to be arthritogenic and induce bone destruction when introduced directly into the joint. Here, we aim to investigate the importance of S. aureus Lpp and TLR2 in a hematogenous septic arthritis model, which is the most common route of infection in humans. C57BL/6 wild-type and TLR2 deficient mice were intravenously inoculated with S. aureus Newman parental strain or its lipoprotein-deficient Δlgt mutant strain. the clinical course of septic arthritis, radiological changes, and serum levels of cytokines and chemokines, were assessed. newman strain induced more severe and frequent clinical septic polyarthritis compared to its Δlgt mutant in TLR2 deficient mice, but not in wild-type controls. Bone destruction, however, did not differ between groups. Lpp expression was associated with higher mortality, weight loss as well as impaired bacterial clearance in mouse kidneys independent of TLR2. Furthermore, Lpp expression induced increased systemic pro-inflammatory cytokine and neutrophil chemokine release. Staphylococcal Lpp are potent virulence factors in S. aureus systemic infection independent of host TLR2 signalling. However, they have a limited impact on bone erosion in hematogenous staphylococcal septic arthritis. Septic arthritis remains a devastating and invasive joint disease. Due to its rapidly progressing nature, septic arthritis is considered a medical emergency 1 with a poor prognosis. Despite advances in understanding and treatment of infectious diseases, the prospect of patients with septic arthritis has remained poor. Almost half of the patients will suffer from permanent joint destruction 2 , if treatment is not initiated immediately 3. The estimated incidence of septic arthritis in the general population is approximately 6-10 cases per 100,000 individuals per year 4. However, in patients with an underlying joint disease, such as rheumatoid arthritis (RA), the incidence of septic arthritis is nearly 10 times higher than in the general population 4. Septic arthritis is most often caused by Staphylococcus aureus (S. aureus), a pathogenic Gram-positive bacterium 5. S. aureus-induced septic arthritis has been extensively studied for the past few decades; several virulence factors as well as various host-factors targeted by the bacterium have been identified 6-11. However, much still remains elusive regarding the bacteria-host interaction in S. aureus septic arthritis. Staphylococcal lipoproteins (Lpp), important bacterial molecules in S. aureus, consist of a lipid-moiety and a protein-part, and are anchored in the bacterial cytoplasmic membrane 12. Lpp are important for bacterial survival during infection due to their role in maintaining the metabolic activity of the bacteria 13,14. The lipid structure of Lpp is known to stimulate the innate immune system through activation of pattern recognition receptors 15 , and bacte...

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“…For instance, after intra-articular injection of S. aureus , RAGE deficiency significantly attenuated the frequency and severity of septic arthritis in one study [73]. However, RAGE deficiency did not affect disease in another study [74] and did also not affect osteoclast differentiation and function in antigen-induced arthritis (AIA) [75]. Nevertheless, most studies point towards the anti-inflammatory effects of sRAGE.…”

Section: Discussionmentioning

confidence: 99%

Relevance of Receptor for Advanced Glycation end Products (RAGE) in Murine Antibody-Mediated Autoimmune Diseases

Eichhorst

Daniel

Rzepka

et al. 2019

IJMS

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It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE−/− animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE−/− mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE−/− animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.

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RAGE Deficiency Impairs Bacterial Clearance in Murine Staphylococcal Sepsis, but Has No Significant Impact on Staphylococcal Septic Arthritis

Cited by 9 publications

References 40 publications

Baicalin modulates apoptosis via RAGE, MAPK, and AP-1 in vascular endothelial cells during Haemophilus parasuis invasion

Baicalin modulates apoptosis via RAGE, MAPK, and AP-1 in vascular endothelial cells during Haemophilus parasuis invasion

The role of Staphylococcus aureus lipoproteins in hematogenous septic arthritis

Relevance of Receptor for Advanced Glycation end Products (RAGE) in Murine Antibody-Mediated Autoimmune Diseases

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