Regulation of lung injury and repair by Toll-like receptors and hyaluronan

Jiang, Dianhua; Liang, Jiurong; Fan, Juan; Yu, Shuang; Chen, Suping; Luo, Yi; Prestwich, Glenn D.; Mascarenhas, Marcella M.; Garg, Hari G.; Quinn, Deborah A.; Homer, Robert J.; Goldstein, Daniel R.; Bucala, Richard; Lee, Patty J; Medzhitov, Ruslan; Noble, Paul W.

doi:10.1038/nm1315

Cited by 1,236 publications

(1,221 citation statements)

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“…The transcription factor NFκB is a key signalling molecule functioning in the innate response of the urogenital cells to flagellin11 and the response to HA 33. The signalling responses of VK2 E6/E7 and RT4 cells are comparable in their NFκB response to flagellin11; therefore, to further explore the signalling mechanisms underpinning the HA/flagellin effects, urothelial cells stably engineered to contain an NFκB reporter were used.…”

Section: Resultsmentioning

confidence: 99%

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

et al. 2018

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ObjectivesRecurrent urinary tract infections are associated with uropathogenic Escherichia coli (UPEC) ascending and infecting the urinary tract. Antibiotics provide only symptomatic relief, not prevent recurrence. Clinical evidence suggests that intravesical glycosaminoglycan therapy, such as hyaluronic acid (HA), helps reduce UTI recurrence. This has been investigated here using in vitro systems modelling the urogenital tract tissues.Methods RT4 bladder cells were preconditioned with high molecular weight HA (> 1500 kDa) at 2 mg mL−1 and challenged with UPEC to analyse barrier protection and bacterial adherence. Untreated and HA‐preconditioned VK2 E6/E7 vaginal cells were challenged with E. coli flagellin (50 ng mL−1) to mimic bacterial challenge, and media analysed for lipocalin‐2, human β‐defensin 2 and interleukin‐8 by ELISA. Experiments were repeated after siRNA knockdown of Toll‐like receptors 2, 4 and 5, and CD44 to investigate signalling.ResultsMicroscopic analyses showed reduced bacterial adherence and urothelial disruption with HA, suggesting that HA functions as a barrier protecting the epithelium from bacterial infection. Cells treated with HA and flagellin simultaneously produced more of the host antimicrobial peptide LCN2 and pro‐inflammatory IL‐8 (P < 0.05) compared to the no HA/flagellin challenges. Increased gene expression of DEFB4 (P < 0.05), but not the hBD2 peptide, was observed in the HA/flagellin‐challenged cells.ConclusionThese data suggest that exogenous HA has potential to protect the urogenital epithelia from UPEC infection via a two‐pronged approach that involves the physical enhancement of the epithelial barrier and augmentation of its innate immune response.

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Section: Resultsmentioning

confidence: 99%

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

et al. 2018

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“…Bacteriocidal reactive oxygen species production is regulated by the interaction of S100A8 and cofactors of Nox2, such as p67 and Rac2 (Kerkhoff et al, 2005) or a direct binding between TLR4 and Nox4 (Park et al, 2004). TLR4 and another proposed endogenous ligand hyaluronan have been shown to regulate lung injury and repair (Jiang et al, 2005). The recent knockout study of CC10, a xenobiotic protein produced in Clara cells against air-borne pollutants, showed upregulation of S100A8 (Saha et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

et al. 2011

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We have previously shown that tumor necrosis factor (TNF)a produced from primary tumor-induced expression of two endogenous Toll-like receptor 4 (TLR4) ligands, S100A8 and serum amyloid A3 (SAA3), in pre-metastatic lungs. However, mechanistic details of the signaling network and relevance to pulmonary physiology are poorly understood. Here, we identify Clara cells as a control tower of the network. Clara cell ablation by naphthalene suppressed pulmonary recruitment of CD11b þ TLR4 þ cells and spontaneous lung metastasis. Clara cells turned out to express TLR4 through which SAA3 was auto-amplified. Reciprocal bone marrow transplantation between wild-type and TLR4 knockout mice demonstrated that pulmonary TLR4 þ Clara cells could be derived from bone marrow. SAA3-induced TNFa expression in both alveolar type II cells and macrophages. Primary co-cultures of alveolar type II cells and Clara cells revealed that the induction of TNFa in alveolar type II cells was dependent on the Clara cell-mediated amplification of SAA3. SAA3 induction by bacterial endotoxin also required both Clara cells and TLR4. Thus, pulmonary metastatic soil may feature deregulation of homeostatic inflammatory responses to constant assaults of microbes with endotoxin.

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“…These include HMGB1 76 31, uric acid 77 , some HSPs 78 79, some defensins [G] 80 , hyaluronic acid 81 , heparan sulfate 82 , and some fragments of extracellular matrix proteins 70 . Whereas this data may well be correct, caution is warranted because TLRs can be stimulated by microbial contaminants that are easily introduced during the purification of molecules.…”

Section: Receptors For Dampsmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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When a cell dies in vivo the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes, that is, it is part of normal physiological processes, then there is little threat to the organism. In this situation, little else is done other than removing the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized. The importance of this process to host defence and disease pathogenesis has only been appreciated relatively recently. This article will review our current knowledge of these processes.The immune system was recognized in ancient times and rediscovered by Jenner and Pasteur based on its ability to confer protection upon repeat exposure to a pathogen. Through subsequent studies by Von Behring and others it rapidly became apparent that the immune system had the potential to respond not only to whole microorganisms, but to virtually any molecule that was "foreign" to the host. However, whereas injection of such molecules would often provoke a robust immune response, this did not invariably occur. Immunization protocols improved in the 1920s with the discovery by Ramon and Glenny of immunostimulatory molecules (adjuvants [G]) that could boost immune responses to co-administered antigens. Adjuvants were typically of microbial origin and became widely used to promote the effectiveness of immunizations. In the 1960s, Dresser showed that a foreign protein when highly purified would only elicit an immune response if it was admixed with a microbial adjuvant 1 . Injected by itself, the antigen not only failed to elicit immunity but actually induced a state of tolerance 2 . However, the significance of these observations was not well appreciated and adjuvants remained one of those things that everyone used because they were part of standard operating procedures.In 1989 Janeway put these empirical observations into a conceptual framework 3 (Fig. 1). He proposed that the immune system did not respond to all foreign antigens but only to those that are potentially associated with infection. The underlying idea here was that the immune system evolved to protect organisms against microorganisms and this discrimination between infectious versus noninfectious antigens focused defences on real threats rather than innocuous situations.At this time, it was already recognized that in order to stimulate T cell responses, antigens had to first be acquired and presented on MHC molecules of an antigen presenting cell (APC). Moreover, it was further known that APCs also provided additional costimulatory signals necessary to activate T cells. Janeway incorporated these principles into his model (Fig. 1). He postulated that the discrimination between infectious and noninfectious non-self molecules was made by the APCs of the innate immune system through receptors that would recognize pathogen-associated molecular patterns (PAMP...

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Regulation of lung injury and repair by Toll-like receptors and hyaluronan

Cited by 1,236 publications

References 38 publications

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

How dying cells alert the immune system to danger

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