scholarly journals Expression of human TLR4/myeloid differentiation factor 2 directs an early innate immune response associated with modest increases in bacterial burden during Coxiella burnetii infection

2019 ◽  
Vol 25 (7) ◽  
pp. 401-411
Author(s):  
Amanda Robison ◽  
Deann T Snyder ◽  
Kelly Christensen ◽  
Emily Kimmel ◽  
Adeline M Hajjar ◽  
...  
Keyword(s):  
Coxiella Burnetii ◽  
Hematopoietic Cells ◽  
Adaptor Protein ◽  
Myeloid Differentiation ◽  
Target Cells ◽  
Lung Pathology ◽  
Bacterial Burden ◽  
Wild Type ◽  
Differentiation Factor ◽  
Myeloid Differentiation Factor

Human TLR4 (hTLR4) and mouse TLR4 molecules respond differently to hypo-acylated LPS. The LPS of Coxiella burnetii is hypo-acylated and heavily glycosylated and causes a minimal response by human cells. Thus, we hypothesized that mice expressing hTLR4 molecules would be more susceptible to C. burnetii infection. Our results show that transgenic mice expressing hTLR4 and the human myeloid differentiation factor 2 (MD-2) adaptor protein (hTLR4/MD-2) respond similarly to wild type mice with respect to overall disease course. However, differences in bacterial burdens in tissues were noted, and lung pathology was increased in hTLR4/MD2 compared to wild type mice. Surprisingly, bone marrow chimera experiments indicated that hTLR4/MD-2 expression on non-hematopoietic cells, rather than the target cells for C. burnetii infection, accounted for increased bacterial burden. Early during infection, cytokines involved in myeloid cell recruitment were detected in the plasma of hTLR4/MD2 mice but not wild type mice. This restricted cytokine response was accompanied by neutrophil recruitment to the lung in hTLR4/MD2 mice. These data suggest that hTLR4/MD-2 alters early responses during C. burnetii infection. These early responses are precursors to later increased bacterial burdens and exacerbated pathology in the lung. Our data suggest an unexpected role for hTLR4/MD-2 in non-hematopoietic cells during C. burnetii infection.

scholarly journals Toll-like Receptor 4-Myeloid Differentiation Factor 88 Signaling Contributes to Ventilator-induced Lung Injury in Mice

2010 ◽  
Vol 113 (3) ◽  
pp. 619-629 ◽  
Author(s):  
Huihua Li ◽  
Xiaoli Su ◽  
Xuebin Yan ◽  
Karla Wasserloos ◽  
Wei Chao ◽  
...  
Keyword(s):  
Lung Injury ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Ventilator Induced Lung Injury ◽  
Differentiation Factor ◽  
Extracellular Signal ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor

Background The mechanisms of ventilator-induced lung injury, an iatrogenic inflammatory condition induced by mechanical ventilation, are not completely understood. Toll-like receptor 4 (TLR4) signaling via the adaptor protein myeloid differentiation factor 88 (MyD88) is proinflammatory and plays a critical role in host immune response to invading pathogen and noninfectious tissue injury. The role of TLR4-MyD88 signaling in ventilator-induced lung injury remains incompletely understood. Methods Mice were ventilated with low or high tidal volume (HTV), 7 or 20 ml/kg, after tracheotomy for 4 h. Control mice were tracheotomized without ventilation. Lung injury was assessed by: alveolar capillary permeability to Evans blue albumin, wet/dry ratio, bronchoalveolar lavage analysis for cell counts, total proteins and cytokines, results of histopathological examination of the lung, and plasma cytokine levels. Results Wild-type mice subjected to HTV had increased pulmonary permeability, inflammatory cell infiltration/lung edema, and interleukin-6/macrophage-inflammatory protein-2 in the lavage compared with control mice. In HTV, levels of inhibitor of kappaB alpha decreased, whereas phosphorylated extracellular signal-regulated kinases increased. TLR4 mutant and MyD88 mice showed markedly attenuated response to HTV, including less lung inflammation, pulmonary edema, cell number, protein content, and the cytokines in the lavage. Furthermore, compared with wild-type mice, both TLR4 mutant and MyD88 mice had significantly higher levels of inhibitor of kappaB alpha and reduced extracellular signal-regulated kinase phosphorylation after HTV. Conclusions TLR4-MyD88 signaling plays an important role in the development of ventilator-induced lung injury in mice, possibly through mechanisms involving nuclear factor-kappaB and mitogen-activated protein kinase pathways.

scholarly journals A MyD88-Deficient Mouse Model Reveals a Role for Nramp1 in Campylobacter jejuni Infection

2007 ◽  
Vol 75 (4) ◽  
pp. 1994-2003 ◽  
Author(s):  
Robert O. Watson ◽  
Veronica Novik ◽  
Dirk Hofreuter ◽  
María Lara-Tejero ◽  
Jorge E. Galán
Keyword(s):  
Campylobacter Jejuni ◽  
Virulence Genes ◽  
Potential Role ◽  
Bacterial Pathogen ◽  
Adaptor Protein ◽  
Myeloid Differentiation ◽  
Deficient Mouse ◽  
Immunocompetent Mice ◽  
Myeloid Differentiation Factor ◽  
Deficient Mice

ABSTRACT Campylobacter jejuni is a major worldwide cause of enteric illnesses. Adult immunocompetent mice are not susceptible to C. jejuni infection. However, we show here that mice deficient in the adaptor protein myeloid differentiation factor 88 (MyD88), which is required for signaling through most Toll-like receptors, can be stably colonized by C. jejuni but not by isogenic derivatives carrying mutations in known virulence genes. We also found that Nramp1 deficiency increases the mouse susceptibility to C. jejuni infection when administered systemically. These results indicate that MyD88-deficient mice could be a useful model to study C. jejuni colonization and reveal a potential role for Nramp1 in the control of this bacterial pathogen.

scholarly journals Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88

2020 ◽  
pp. 175342592092747
Author(s):  
Yajie Yang ◽  
Yan Hu ◽  
Yile Zhou ◽  
Tao Liang ◽  
Haihong Tang ◽  
...  
Keyword(s):  
Inflammatory Factors ◽  
Myeloid Differentiation ◽  
Study Group ◽  
Tlr4 Expression ◽  
Wild Type ◽  
Human Embryonic Kidney ◽  
Gram Negative ◽  
Tnf Α ◽  
Polymorphic Variants ◽  
Myeloid Differentiation Factor

TLR4 polymorphisms such as Asp299Gly and Thr399Ile related to Gram-negative sepsis have been reported to result in significantly blunted responsiveness to LPS. Our study group previously screened other TLR4 polymorphic variants by checking the NF-κB activation in comparison to wild type (WT) TLR4 in human embryonic kidney 293T cells. In this study, we found that the Lys694Arg (K694R) polymorphism reduced the activation of NF-κB, and the production of downstream inflammatory factors IL-1, TNF-α and IL-6, representing the K694R polymorphism, led to blunted responsiveness to LPS. Then, we examined the influence of the K694R polymorphism on total and cell-surface TLR4 expression by Western blotting and flow cytometry, respectively, but observed no differences between the K694R polymorphism and WT TLR4. We also used co-immunoprecipitation to determine the interaction of the K694R polymorphism and WT TLR4 with their co-receptor myeloid differentiation factor 2 (MD2) and their downstream signal adaptor MyD88. We found that K694R reduced the recruitment of MyD88 in TLR4 signalling but had no impact on the interaction with MD2.

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