Jiang, D, Liang, J, Fan, J, Yu, S, Chen, S, Luo, Y et al.. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 11: 1173-1179

Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
Nature Medicine (Impact Factor: 27.36). 12/2005; 11(11):1173-9. DOI: 10.1038/nm1315
Source: PubMed


Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.

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    • "HA is an ubiquitous linear polysaccharide assembled at the inner plasma membrane by HA synthases (HAS) [35] [36]. HAS1 and HAS2 synthesize HA with a molecular mass of 2 x 10 5 Da to approximately 2 x 10 6 Da, whereas HAS3 synthesizes HA with a molecular mass of 1 x 10 5 to 1 x 10 6 Da [37] which in turn activate Toll-like receptors 2 and 4 modulating inflammatory responses [38] [39]. In the skin, HA plays a variety of important physiological roles in tissue hydration and mechanical protection due to its physicochemical properties such as strong hydration and viscoelasticity [40]. "
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    ABSTRACT: Excessive exposure to the sun can cause severe photoaging as early as the second decade of life resulting in a loss of physiological elastic fiber functions. We designed a study to test the hypothesis that a dietary supplement would improve facial photoaging, also promoting changes in the serum levels of fibronectin, elastin, neutrophil elastase 2, hyaluronic acid and carbonylated proteins.
    Full-text · Article · Jan 2015
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    • "Likewise, treatment of KC with hyaluronidase, which results in very small oligosaccharides, reduced the effect of contact allergens on IL-18 production, further supporting the role of HA degradation in KC activation. This is well in accord with previous studies demonstrating that, the effect of HA on the inflammatory response appears to be strictly related to its molecular size, i.e. larger HA has anti-inflammatory activity while smaller HA has pro-inflammatory activity (Jiang et al., 2005; Yamawaki et al., 2009; Pasonen-Seppänen et al., 2012). LMWHA increased TLR-4, MyD88, TRAF-6, iNOS, MMP-13 expression and pro-inflammatory cytokines Il-1b and IL-8 expression, modulating both innate and acquired immune response of these cells (Campo et al., 2010). "
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    ABSTRACT: Interleukin-18 (IL-18) has been shown to play a key proximal role in the induction of allergic contact dermatitis. Low molecular weight hyaluronan (LMWHA), an endogenous molecule and a member of the so-called damage associated molecular patterns (DAMPs), has been suggested to elicit immune-stimulatory effects. The purpose of this study was to examine the role of hyaluronan (HA) degradation in IL-18 production in human keratinocytes following stimulation with the contact sensitizers 2,4-dinitrochlorobenzene (DNCB) and PPD. IL-18 production in the human keratinocyte cell line NCTC2544 was measured by ELISA, whereas changes in HA metabolism were determined by Real-time PCR and immunofluorescence. Both contact allergens were able to enhance hyaluronidase (HYAL) 1 and 2 expression inducing HA degradation. Modulation of HA production, by HYAL or aristolochic acid pre-treatment, resulted in a significant reduction of contact allergen-induced IL-18 production. Oxidative stress appears to be the initial step in KC activation, as all the sequels of events can be blocked using antioxidants. This is the first indication that LMWHA can act as a DAMP in keratinocytes. In conclusion LMWHA fragments are important mediators in the process of contact sensitisation leading to IL-18 dependent responses.
    Full-text · Article · Sep 2014 · Toxicology Letters
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    • "The effects of these polymers with different molecular weight are markedly different triggering different signaling pathways including NF-κB and ERK phosphorylation [51]. The hypothesis proposed so far is the capacity of HMW to cluster the receptors on cell membrane, modulating in this way the receptor activity [49]. If LMW hyaluronan interacts with the receptors on cell membrane it is unable to gather the proteins on the cell membrane and the signaling differs strongly from that induced by HMW on the same cells. "
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    ABSTRACT: Background Hyaluronan is a critical component of extracellular matrix with several different roles. Besides the contribution to the tissue hydration, mechanical properties and correct architecture, hyaluronan plays important biological functions interacting with different molecules and receptors. Scope of review The review addresses the control of hyaluronan synthesis highlighting the critical role of hyaluronan synthase 2 in this context as well as discussing the recent findings related to covalent modifications which influence the enzyme activity. Moreover, the interactions with specific receptors and hyaluronan are described focusing on the importance of polymer size in the modulation of hyaluronan signaling. Major conclusions Due to its biological effects on cells recently described, it is evident how hyaluronan is to be considered not only a passive component of extracellular matrix but an actor involved in several scenarios of cell behavior. General significance The effects of metabolism on the control of hyaluronan synthesis both in healthy and pathologic conditions are critical and still not completely understood. The hyaluronan capacity to bind several receptors triggering specific pathways may represent a valid target for new approach in several therapeutic strategies. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
    Full-text · Article · Aug 2014 · Biochimica et Biophysica Acta (BBA) - General Subjects
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