Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release

Dagvadorj, Jargalsaikhan; Shimada, Kenichi; Chen, Shuang; Jones, Heather D.; Tumurkhuu, Gantsetseg; Zhang, Wenxuan; Wawrowsky, Kolja; Crother, Timothy R.; Arditi, Moshe

doi:10.1016/j.immuni.2015.03.007

Cited by 114 publications

(103 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These mice have normal MyD88 function except in their vascular ECs where exon 3 of MyD88 is removed by the cre recombinase, thus making them unresponsive to TLR/MyD88 signaling, as well as IL-1α/β signaling (Supplemental Figure III). 40 We found that the endothelial MyD88 conditional knockout mice (EC Myd88−/− ) were not protected and developed KD vasculitis with no differences compared to WT mice (Fig. 7A–C).…”

Section: Resultsmentioning

confidence: 88%

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Lee

Wakita

Dagvadorj

et al. 2015

ATVB

Self Cite

104

View full text Add to dashboard Cite

Objective Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and IL-1β signaling are required for the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c+ Dendritic Cells (DCs) and macrophages and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling in LCWE-induced KD mouse model of vasculitis. Approach and Results Using mouse knockout models as well as antibody depletion, we found that both IL-1α and IL-1β were required for LCWE-induced KD. Both DCs and macrophages were necessary and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling was critically required in non-endothelial stromal cells, but not hematopoietic cells. Conclusions Our results suggest that IL-1α and IL-1β as well as CD11c+ DCs and macrophages are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, while IL-1 signaling and response is required only in stromal cells, but not in endothelial cells. Determining the role IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.

show abstract

Section: Resultsmentioning

confidence: 88%

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Lee

Wakita

Dagvadorj

et al. 2015

ATVB

Self Cite

104

View full text Add to dashboard Cite

show abstract

“…Alternatively, Dagvadorj and colleagues showed that lipopolysaccharide (LPS) drives alveolar macrophage cell death and IL-1␣ release through a P2X7R-dependent mechanism (46). Thus, we wanted to test whether or not P2X7R was necessary for IL-1␣ release following A. fumigatus challenge.…”

Section: Resultsmentioning

confidence: 99%

Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates

et al. 2017

View full text Add to dashboard Cite

Heterogeneity among Aspergillus fumigatus isolates results in unique virulence potential and inflammatory responses. How these isolates drive specific immune responses and how this affects fungally induced lung damage and disease outcome are unresolved. We demonstrate that the highly virulent CEA10 strain is able to rapidly germinate within the immunocompetent lung environment, inducing greater lung damage, vascular leakage, and interleukin 1␣ (IL-1␣) release than the low-virulence Af293 strain, which germinates with a lower frequency in this environment. Importantly, the clearance of CEA10 was consequently dependent on IL-1␣, in contrast to Af293. The release of IL-1␣ occurred by a caspase 1/11-and P2XR7-independent mechanism but was dependent on calpain activity. Our finding that early fungal conidium germination drives greater lung damage and IL-1␣-dependent inflammation is supported by three independent experimental lines. First, pregermination of Af293 prior to in vivo challenge drives greater lung damage and an IL-1␣-dependent neutrophil response. Second, the more virulent EVOL20 strain, derived from Af293, is able to germinate in the airways, leading to enhanced lung damage and IL-1␣-dependent inflammation and fungal clearance. Third, primary environmental A. fumigatus isolates that rapidly germinate under airway conditions follow the same trend toward IL-1␣ dependency. Our data support the hypothesis that A. fumigatus phenotypic variation significantly contributes to disease outcomes.

show abstract

“…Once bound, CD14 chaperones these pathogenic molecules to the correct TLR, and today, CD14 has been shown to be a coreceptor, not only for TLR2 and TLR4 but also, at least for mice, for TLR3, -7, and -9 [46,48]. CD14 is also implicated in LPS signaling through non-TLRs, such as the purinergic P2X7 receptor for ATP [49]. Thus, CD14 is of utmost interest as a bottleneck-target goal at the recognition phase of innate immunity.…”

Section: Tlr Inhibitionmentioning

confidence: 99%

Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases—C3 or C5 emerge together with CD14 as promising targets

Barratt‐Due

Pischke

Nilsson

et al. 2016

Journal of Leukocyte Biology

View full text Add to dashboard Cite

show abstract

Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release

Cited by 114 publications

References 70 publications

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates

Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases—C3 or C5 emerge together with CD14 as promising targets

Contact Info

Product

Resources

About