CD44 Is a Negative Regulator of Acute Pulmonary Inflammation and Lipopolysaccharide-TLR Signaling in Mouse Macrophages

Liang, Jiurong; Jiang, Dianhua; Griffith, Jason W.; Yu, Shuang; Fan, Juan; Zhao, Xiaojie; Bucala, Richard; Noble, Paul W.

doi:10.4049/jimmunol.178.4.2469

Cited by 121 publications

(131 citation statements)

References 41 publications

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“…Thus, we generated LPS-sublethal shock models of CD44Ϫ/Ϫ and CD44ϩ/ϩ mice. Surprisingly, CD44Ϫ/Ϫ mice displayed dramatic hypersensitivity to LPS compared with CD44ϩ/ϩ mice (data not shown), consistent with data in a recent report (36). From this finding, it is clear that CD44 plays an indispensable role in the regulation of TLRmediated responses in vivo.…”

Section: Discussionsupporting

confidence: 82%

CD44 Suppresses TLR-Mediated Inflammation

Kawana

Karaki

Higashi

et al. 2008

The Journal of Immunology

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The cell adhesion molecule CD44, which is the major hyaluronan receptor, has been implicated in the binding, endocytosis, and metabolism of hyaluronan. Previous studies have revealed that CD44 plays crucial roles in a variety of inflammatory diseases. In recent years, TLRs, which are ancient microbial pattern recognition receptors, have been shown to initiate an innate immune response and have been linked to a variety of inflammatory diseases. The present study shows that CD44 negatively regulates in vivo inflammation mediated by TLRs via NF-κB activation, which leads to proinflammatory cytokine production. Furthermore, our results show that CD44 directly associates with TLR2 when stimulated by the TLR2 ligand zymosan and that the cytoplasmic domain of CD44 is crucial for its regulatory effect on TLR signaling. This study indicates that CD44 plays a protective role in TLR-mediated inflammation and is the first to demonstrate a direct association between CD44 and a TLR.

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Section: Discussionsupporting

confidence: 82%

CD44 Suppresses TLR-Mediated Inflammation

Kawana

Karaki

Higashi

et al. 2008

The Journal of Immunology

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“…The importance of the cell adhesion receptor molecule CD44 in this process has been further demonstrated in vivo using CD44 −/− mice, with the accumulation of LMW HA associated with and responsible for an exaggerated inflammatory response 46, 47. Consistent with the reported properties of HMW HA, its application to urothelial cells was not associated with inflammation as measured by either NFκB signalling or immune effector synthesis.…”

Section: Discussionsupporting

confidence: 52%

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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“…In contrast, other investigations did not support an essential role for CD44 in mediating leukocyte infiltration in inflamed tissues, but suggested that CD44-hyaluronan interactions are important for suppression of inflammation and resolution of the inflammatory infiltrate. CD44 KO animals exhibited accentuated inflammation in a model of collagen-induced arthritis (28), were more susceptible to endotoxin-induced shock (29), and showed enhanced neutrophil migration and lung injury in murine bacterial pneumonia (30). In vitro experiments demonstrated that CD44 Ϫ/Ϫ neutrophils migrate faster through matrigel than WT neutrophils, suggesting that CD44 may slow neutrophil migration through extracellular matrix (30).…”

Section: The Role Of Cd44 In Regulation Of the Postinfarction Inflammmentioning

confidence: 96%

“…These actions may be due to CD44-induced intracellular signaling events in leukocytes bound to hyaluronan or other ligands (30). In addition, CD44 may prevent exaggerated inflammatory responses by promoting the expression of negative regulators of TLR-4 signaling (29). Furthermore, CD44 null animals succumb to unremitting inflammation following noninfectious lung injury (6) demonstrating impaired clearance of apoptotic neutrophils and hyaluronan fragments.…”

Section: The Role Of Cd44 In Regulation Of the Postinfarction Inflammmentioning

confidence: 99%

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

Huebener

Abou-Khamis

Zymek

et al. 2008

The Journal of Immunology

160

151

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Infarct healing is dependent on an inflammatory reaction that results in leukocyte infiltration and clearance of the wound from dead cells and matrix debris. However, optimal infarct healing requires timely activation of “stop signals” that suppress inflammatory mediator synthesis and mediate resolution of the inflammatory infiltrate, promoting formation of a scar. A growing body of evidence suggests that interactions involving the transmembrane receptor CD44 may play an important role in resolution of inflammation and migration of fibroblasts in injured tissues. We examined the role of CD44 signaling in infarct healing and cardiac remodeling using a mouse model of reperfused infarction. CD44 expression was markedly induced in the infarcted myocardium and was localized on infiltrating leukocytes, wound myofibroblasts, and vascular cells. In comparison with wild-type mice, CD44−/− animals showed enhanced and prolonged neutrophil and macrophage infiltration and increased expression of proinflammatory cytokines following myocardial infarction. In CD44null infarcts, the enhanced inflammatory phase was followed by decreased fibroblast infiltration, reduced collagen deposition, and diminished proliferative activity. Isolated CD44null cardiac fibroblasts had reduced proliferation upon stimulation with serum and decreased collagen synthesis in response to TGF-β in comparison to wild-type fibroblasts. The healing defects in CD44−/− mice were associated with enhanced dilative remodeling of the infarcted ventricle, without affecting the size of the infarct. Our findings suggest that CD44-mediated interactions are critically involved in infarct healing. CD44 signaling is important for resolution of the postinfarction inflammatory reaction and regulates fibroblast function.

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CD44 Is a Negative Regulator of Acute Pulmonary Inflammation and Lipopolysaccharide-TLR Signaling in Mouse Macrophages

Cited by 121 publications

References 41 publications

CD44 Suppresses TLR-Mediated Inflammation

CD44 Suppresses TLR-Mediated Inflammation

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

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

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