Erlotinib protects against LPS-induced Endotoxicity because TLR4 needs EGFR to signal

De, Sajal; Zhou, Hao; DeSantis, David; Croniger, Colleen M.; Li, Xiaoxia; Stark, George R.

doi:10.1073/pnas.1511794112

Cited by 78 publications

(83 citation statements)

References 61 publications

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“…In this sense, AT 1 R activation has been reported to promote the transactivation of EGF receptors (EGFRs) (69). EGFR signaling is required for TLR4-mediated activation of NF-B in response to lipopolysaccharide (20), and its activation by ANG II can occur within a similar time course (in minutes) as the effect we describe here for ANG II-TLR4-ROS production. Another possibility is that ANG II induces the upregulation and activation of the cytokine transforming growth factor-␤ by trombospondin-1 (36), which, in turn, activates TLR4 pathways in macrophages to induce TNF-␣ production (42).…”

Section: Tlr4 In Microglia Is Involved In Ang Ii-mediated Ros Within supporting

confidence: 55%

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Biancardi

Stranahan

Krause

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

106

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II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT 1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (ϳ65% increase, P Ͻ 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P Ͻ 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT 1a knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT 1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN. ANGIOTENSIN II (ANG II) plays a critical role in fluid balance and hemodynamic regulation (25). Within the central nervous system (CNS), ANG II acting through ANG II type 1 a (AT 1a ) receptors (AT 1a R) has been shown to be implicated in the regulation of sympathetic and neuroendocrine outputs from the brain (45, 49, 50). The paraventricular nucleus (PVN) of the hypothalamus has been recognized as a critical neuronal substrate mediating central ANG II actions, thus playing a critical role in ANG II-mediated neurohumoral responses (23, 78). Indeed, a large body of evidence supports enhanced angiotensinergic actions within the CNS, including the PVN, as a key pathophysiological mechanism involved in cardiovascular diseases, including hypertension and heart failure (37,60,78,80,88). However, despite its importance, the precise mechanisms and cellular/ molecular targets underlying ANG II signaling within the CNS are incompletely understood.Inflammation and oxidative stress have emerged as novel mechanisms by which central ANG II mediates its deleterious effects. For example, studies have shown that pressor and sympathetic responses to central ANG II are mediated by superoxide within the PVN (8, 22). Likewise, several studie...

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Section: Tlr4 In Microglia Is Involved In Ang Ii-mediated Ros Within supporting

confidence: 55%

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Biancardi

Stranahan

Krause

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

106

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“…Quantitative real-time PCR was performed as described previously (32). cDNA was synthesized from total RNA, using a random hexamer and SuperScript III …”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting Tumor-Initiating Cells

Lindner

Coleman

et al. 2018

Cancer Research

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Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically.In response to CBL0137 alone, TIC were more sensitive than non-TIC, in part because CBL0137 increased expression of the tumor suppressor NOTCH1 by abrogating the binding of negative regulator SP3 to the NOTCH1 promoter, and in part because treatment decreased the high expression of stem cell transcription factors. The combination of cisplatin and CBL0137 greatly reduced the growth of a patient-derived xenograft in mice and also the growth of a syngeneic mouse SCLC tumor. Thus, CBL0137 can be a highly effective drug against SCLC, especially in combination with cisplatin. Statement of SignificanceFindings reveal a novel therapeutic regimen for SCLC combining cisplatin with an inhibitor that preferentially targets tumor-initiating cells.

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“…20 Although the mechanism is unclear, the EGFR inhibitor erlotinib blocks LPSinduced expression of tumor necrosis factor a (TNFa) and interleukin-6 (IL-6), while attenuating LPS-induced endotoxicity, indicating that the EGFR is essential for LPS-induced signaling in vivo.…”

Section: Tlr4 Signaling In Wound Repairmentioning

confidence: 99%

“…Gefitinib and erlotinib reduce pulmonary damage and promote increased survival in mouse models of sepsis, 20,21 while erlotinib blunts the proinflammatory and proliferative responses following hepatic injury.…”

mentioning

confidence: 99%

“…[22][23][24][25] Linkages, however, are unclear and interactions between TLR4 and EGFR may be functional as complexes between the two receptors have not been detected. 20,21 Integrins are also implicated in pathogen-induced TLR activation; such cooperation occurs in both immune and nonimmune cells where integrins enhance the innate immune response. Certain integrins may serve as TLR coreceptors, binding directly to ligands to initiate TLR signaling.…”

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confidence: 99%

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Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program

McKeown‐Longo

Higgins

2017

Advances in Wound Care

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Erlotinib protects against LPS-induced Endotoxicity because TLR4 needs EGFR to signal

Cited by 78 publications

References 61 publications

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting Tumor-Initiating Cells

Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program

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Erlotinib protects against LPS-induced Endotoxicity because TLR4 needs EGFR to signal

Cited by 78 publications

References 61 publications

Cross talk between AT1receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Cross talk between AT1receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting Tumor-Initiating Cells

Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program

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Product

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Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus