Role of TLR- / NLR-signaling and the associated cytokines involved in recruitment of neutrophils in murine models of<i>Staphylococcus aureus</i>infection

Sethi, Shneh; Chakraborty, Trinad

doi:10.4161/viru.2.4.16142

Cited by 22 publications

(22 citation statements)

References 111 publications

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“…is important to understand the complex network of molecules and signaling that is responsible for an inflammatory response. It is now widely accepted that crosstalk between TLR4 and the NLRP3 inflammasome in response to LPS and ATP stimuli is associated with an inflammatory response [4,35,36]. In our previously published reports [14,15], we identified the SPA4 peptide that binds to TLR4 and down-regulates LPS-TLR4-MYD88-NF-kB and the inflammatory cytokine response.…”

Section: Discussionmentioning

confidence: 85%

Toll-like receptor 4-interacting SPA4 peptide suppresses the NLRP3 inflammasome in response to LPS and ATP stimuli

Ramani

Awasthi

2015

Journal of Leukocyte Biology

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Inflammation is induced because of interplay among multiple signaling pathways and molecules during infectious and noninfectious tissue injuries. Crosstalk between Toll-like receptor-4 signaling and the neuronal apoptosis inhibitor protein, major histocompatibility class 2 transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein (NACHT), leucine-rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome against pathogen- or damage-associated molecular patterns can cause exaggerated inflammation. We previously established that the Toll-like receptor-4-interacting SPA4 peptide suppresses gram-negative bacterial lipopolysaccharide (Toll-like receptor-4 ligand)-induced nuclear factor-κB and inflammatory response. In the present study, we hypothesized that the SPA4 peptide exerts its anti-inflammatory effects by suppressing the crosstalk between Toll-like receptor-4 signaling and the NLRP3 inflammasome. We evaluated binding of the lipopolysaccharide-ligand to cell-surface Toll-like receptor-4 in the presence or absence of adenosine triphosphate (an NLRP3 inflammasome inducer) by flow cytometry. The expression and activity of NLRP3 inflammasome-related parameters were studied in cells challenged with lipopolysaccharide and adenosine triphosphate using molecular and immunologic methods. The cells were challenged with lipopolysaccharide and treated with SPA4 peptide before (pre-adenosine triphosphate) or after (post-adenosine triphosphate) secondary challenge with adenosine triphosphate. Our data demonstrate that the Toll-like receptor-4-interacting SPA4 peptide does not affect the binding of lipopolysaccharide to Toll-like receptor-4 in the presence or absence of adenosine triphosphate. We also found that the SPA4 peptide inhibits mRNA and cellular protein levels of pro-interleukin-1β and NLRP3, formation of the NLRP3 inflammasome, caspase activity, and release of interleukin-1β. Furthermore, the SPA4 peptide treatment reduced the secreted levels of interleukin-1β from cells overexpressing Toll-like receptor-4 compared with cells expressing the dominant-negative form of Toll-like receptor-4. Together our results suggest that the SPA4 peptide exerts its anti-inflammatory activity by suppressing Toll-like receptor-4-priming of the NLRP3 inflammasome.

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Section: Discussionmentioning

confidence: 85%

Toll-like receptor 4-interacting SPA4 peptide suppresses the NLRP3 inflammasome in response to LPS and ATP stimuli

Ramani

Awasthi

2015

Journal of Leukocyte Biology

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“…As cytokine production was considerably reduced at time points later than 6 hours in all groups, blockade of HMGB1 from 24 hours onward had only little effect. As such, the brisk induction of inflammatory mediators after intrapulmonary delivery of S. aureus is most likely initiated via a TLR2-MyD88 dependent mechanism [20], while the subsequent release of HMGB1 apparently does not sustain this response, although anti-HMGB1 reduced the already low KC levels in BAL fluid at 48 hours.…”

Section: Discussionmentioning

confidence: 99%

“…We showed that TLR4 is not involved in the lung pathology induced by S. aureus . We did not expect a direct role for TLR4 in the initiation of lung inflammation induced by S. aureus , considering that this pathogen does not express known TLR4 ligands [20]. Of note, however, TLR4 not only can function as a receptor for HMGB1, but also for other DAMPs released upon acute lung injury [22].…”

Section: Discussionmentioning

confidence: 99%

High-mobility group box 1 and the receptor for advanced glycation end products contribute to lung injury during Staphylococcus aureus pneumonia

et al. 2013

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IntroductionStaphylococcus (S.) aureus has emerged as an important cause of necrotizing pneumonia. Lung injury during S. aureus pneumonia may be enhanced by local release of damage associated molecular patterns such as high-mobility group box 1 (HMGB1). In the current study we sought to determine the functional role of HMGB1 and its receptors, toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE), in the injurious host response to S. aureus pneumonia.MethodsPneumonia was induced in wild type (Wt), TLR4 deficient (tlr4−/−) and RAGE deficient (rage−/−) mice by intranasal inoculation of 1 × 107 colony-forming units (CFU) of a USA300 S. aureus. In a separate set of experiments, Wt mice were injected intraperitoneally with a monoclonal anti-HMGB1 antibody or an isotype matched control antibody immediately before and every 24 hours after intranasal infection of S. aureus. Mice were sacrificed at 6, 24, 48 or 72 hours after infection for harvesting of blood and organs.ResultsS. aureus pneumonia was associated with HMGB1 release in the bronchoalveolar compartment peaking after 24 hours. Anti-HMGB1 attenuated lung pathology and protein leak and reduced interleukin-1β release 6 hours after infection, but not at later time points. RAGE deficiency more modestly attenuated lung pathology without influencing protein leak, while TLR4 deficiency did not impact on lung injury.ConclusionThese data suggest that HMGB1 and RAGE, but not TLR4, contribute to lung injury accompanying the early phase of S. aureus pneumonia.

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“…This leads to production of several proinflammatory cytokines, chemokines, and other inflammatory mediators [6, 12–16]. Some studies have shown that staphylococcal PAMPs can even directly activate T cells to a proinflammatory phenotype in a TLR2-Myd88 dependent manner [17], while others have demonstrated that S. aureus and staphylococcal PAMPs are able to override the immune regulatory functions of T regulatory cells, thereby indirectly promoting inflammation [18].…”

Section: Introductionmentioning

confidence: 99%

“…Given that both the SSAg and the staphylococcal PAMPs elicit a predominantly proinflammatory type of immune response [16, 19, 20], it is widely believed that, during invasive S. aureus infections, the PAMPs would act additively or synergistically with SSAg leading to a more pronounced inflammatory response and inflicting severe immunopathology [7, 21]. On the contrary, some recent studies have shown that the staphylococcal cell wall components and certain other staphylococcal PAMPs downregulate the immune response to SSAg as well as dampen antistaphylococcal immunity [22–24].…”

Section: Introductionmentioning

confidence: 99%

The Impact ofStaphylococcus aureus-Associated Molecular Patterns on Staphylococcal Superantigen-Induced Toxic Shock Syndrome and Pneumonia

Tilahun

Karau

Ballard

et al. 2014

Mediators of Inflammation

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Staphylococcus aureus is capable of causing a spectrum of human illnesses. During serious S. aureus infections, the staphylococcal pathogen-associated molecular patterns (PAMPs) such as peptidoglycan, lipoteichoic acid, and lipoproteins and even intact S. aureus, are believed to act in conjunction with the staphylococcal superantigens (SSAg) to activate the innate and adaptive immune system, respectively, and cause immunopathology. However, recent studies have shown that staphylococcal PAMPs could suppress inflammation by several mechanisms and protect from staphylococcal toxic shock syndrome, a life-threatening systemic disease caused by toxigenic S. aureus. Given the contradictory pro- and anti-inflammatory roles of staphylococcal PAMPs, we examined the effects of S. aureus-derived molecular patterns on immune responses driven by SSAg in vivo using HLA-DR3 and HLA-DQ8 transgenic mice. Our study showed that neither S. aureus-derived peptidoglycans (PGN), lipoteichoic acid (LTA), nor heat-killed Staphylococcus aureus (HKSA) inhibited SSAg-induced T cell proliferation in vitro. They failed to antagonize the immunostimulatory effects of SSAg in vivo as determined by their inability to attenuate systemic cytokine/chemokine response and reduce SSAg-induced T cell expansion. These staphylococcal PAMPs also failed to protect HLA-DR3 as well as HLA-DQ8 transgenic mice from either SSAg-induced toxic shock or pneumonia induced by a SSAg-producing strain of S. aureus.

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Role of TLR- / NLR-signaling and the associated cytokines involved in recruitment of neutrophils in murine models ofStaphylococcus aureusinfection

Cited by 22 publications

References 111 publications

Toll-like receptor 4-interacting SPA4 peptide suppresses the NLRP3 inflammasome in response to LPS and ATP stimuli

Toll-like receptor 4-interacting SPA4 peptide suppresses the NLRP3 inflammasome in response to LPS and ATP stimuli

High-mobility group box 1 and the receptor for advanced glycation end products contribute to lung injury during Staphylococcus aureus pneumonia

The Impact ofStaphylococcus aureus-Associated Molecular Patterns on Staphylococcal Superantigen-Induced Toxic Shock Syndrome and Pneumonia

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