CD44 Suppresses TLR-Mediated Inflammation

Kawana, Hiroki; Karaki, Hirokazu; Higashi, Morihiro; Miyazaki, Masaru; Hilberg, Frank; Kitagawa, Motoo; Harigaya, Kenichi

doi:10.4049/jimmunol.180.6.4235

Cited by 84 publications

(84 citation statements)

References 38 publications

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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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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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“…8,9,24,35 This discrepancy is probably because of the differences in the cell type studied, the stimulus and organ involved, and the severity of the insult. We here found no differences in macrophage numbers in BALF of CD44 KO and WT mice during either lethal or sublethal pneumococcal pneumonia, indicating that CD44 does not affect on macrophage recruitment into the bronchoalveolar space induced by S. pneumoniae.…”

Section: Discussionmentioning

confidence: 83%

“…For instance, CD44 KO mice demonstrated increased IL-1b and TNF-a levels in their BALF on a pulmonary LPS challenge, 8 and CD44 KO bone marrow-derived macrophages produced more TNF-a and IL-6 on stimulation with not only LPS but also with ligands for Toll-like receptor (TLR)3, TLR5, TLR7 or TLR9. 35 In these studies, however, single ligands for specific TLRs were used, whereas intact pneumococci express multiple ligands that can stimulate several pathways resulting in cytokine release. Indeed, ex vivo stimulation of CD44 KO alveolar macrophages with S. pneumoniae did not result in different TNF-a release as compared with WT cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia

Windt

Hoogendijk

Vos

et al. 2011

Laboratory Investigation

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Streptococcus pneumoniae is the most prevalent pathogen causing community-acquired pneumonia. CD44 is a transmembrane adhesion molecule, expressed by a wide variety of cell types, that has several functions in innate and adaptive immune responses. In this study, we tested the hypothesis that CD44 is involved in the host response during pneumococcal pneumonia. On intranasal infection with a lethal dose of S. pneumoniae CD44-knockout (KO) mice showed a prolonged survival when compared with wild-type mice, which was accompanied by a diminished pulmonary bacterial growth and reduced dissemination to distant body sites. Whereas, proinflammatory cytokine responses and lung pathology were not affected, CD44 deficiency resulted in increased early neutrophil influx into the lung. In separate experiments, we confirmed a detrimental role of CD44 in host defense against pneumococci during sublethal pneumonia, as demonstrated by an improved capacity of CD44 KO mice to clear a low infectious dose. In addition, CD44 appeared important for the resolution of lung inflammation during sublethal pneumonia, as shown by histopathology of lung tissue slides. In conclusion, we show here that CD44 facilitates bacterial outgrowth and dissemination during pneumococcal pneumonia, which in lethal infection results in a prolonged survival of CD44 KO mice. Moreover, during sublethal pneumonia CD44 contributes to the resolution of the inflammatory response.

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“…Together, these studies suggest an important role for macrophage CD44 in the removal of fragmented hyaluronan from inflammatory sites. Although TLR2 and -4 are thought to be the receptors that activate macrophages and dendritic cells in response to fragmented hyaluronan, CD44 can modulate TLR4 responses by negatively regulating TLR signaling (15,16). Therefore, through the removal of proinflammatory fragmented hyaluronan and down-regulation of TLR signaling, CD44 may dampen the inflammatory response and assist in the resolution of inflammation, as has been observed in the bleomycin model of lung inflammation (14).…”

mentioning

confidence: 94%

Differential Use of Chondroitin Sulfate to Regulate Hyaluronan Binding by Receptor CD44 in Inflammatory and Interleukin 4-activated Macrophages

Ruffell¹,

Poon

Lee³

et al. 2011

Journal of Biological Chemistry

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CD44 is a cell surface receptor for the extracellular matrix glycosaminoglycan hyaluronan and is involved in processes ranging from leukocyte recruitment to wound healing. In the immune system, the binding of hyaluronan to CD44 is tightly regulated, and exposure of human peripheral blood monocytes to inflammatory stimuli increases CD44 expression and induces hyaluronan binding. Here we sought to understand how mouse macrophages regulate hyaluronan binding upon inflammatory and anti-inflammatory stimuli. Mouse bone marrow-derived macrophages stimulated with tumor necrosis factor ␣ or lipopolysaccharide and interferon-␥ (LPS/IFN␥) induced hyaluronan binding by up-regulating CD44 and down-regulating chondroitin sulfation on CD44. Hyaluronan binding was induced to a lesser extent in interleukin-4 (IL-4)-activated macrophages despite increased CD44 expression, and this was attributable to increased chondroitin sulfation on CD44, as treatment with ␤-D-xyloside to prevent chondroitin sulfate addition significantly enhanced hyaluronan binding. These changes in the chondroitin sulfation of CD44 were associated with changes in mRNA expression of two chondroitin sulfotransferases, CHST3 and CHST7, which were decreased in LPS/IFN␥-stimulated macrophages and increased in IL-4-stimulated macrophages. Thus, inflammatory and anti-inflammatory stimuli differentially regulate the chondroitin sulfation of CD44, which is a dynamic physiological regulator of hyaluronan binding by CD44 in mouse macrophages.Macrophages differentiate from peripheral blood monocytes upon recruitment to the tissues. Under homeostatic conditions this process occurs constitutively to maintain a population of resident macrophages that provide a first line of defense against invading microorganisms (for review, see Refs. 1 and 2). This is of particular importance in some tissues, such as the lungs, where phagocytosis of bacteria by resident alveolar macrophages can be sufficient to clear infection (3). During inflammatory conditions, recruitment of a different subpopulation of monocytes occurs, and the number of macrophages in the tissues is greatly increased. Macrophages initially undergo "classical activation" in response to IFN␥ and toll-like receptor (TLR) 6 ligands such as LPS and display increased anti-microbial abilities due to increased production of reactive nitrogen and oxygen species (for review, see Refs. 4 and 5). The production of proinflammatory and T helper cell 1 (T H 1)-polarizing cytokines by these LPS-and IFN␥-polarized (M1) macrophages affects both the local and systemic immune response. Recruited macrophages are also important for resolving inflammation, as they phagocytose inflammation-inducing agents such as bacteria, cellular debris, and degraded extracellular matrix components (6, 7). Furthermore, increased levels of anti-inflammatory or T helper cell 2 (T H 2)-polarizing cytokines such as IL-4 result in the "alternative activation" of macrophages. These alternatively activated (M2) macrophages produce anti-inflammatory cytokines ...

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CD44 Suppresses TLR-Mediated Inflammation

Cited by 84 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?

The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia

Differential Use of Chondroitin Sulfate to Regulate Hyaluronan Binding by Receptor CD44 in Inflammatory and Interleukin 4-activated Macrophages

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