CD44 is necessary for optimal contact allergic responses but is not required for normal leukocyte extravasation.

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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.

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

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151

“…CD44 is constitutively expressed on both hemopoietic and parenchymal cells. A considerable number of publications have reported that CD44 plays crucial roles in a variety of inflammatory diseases (2)(3)(4)(5)(6)(7)(8), in which CD44 expression is up-regulated on inflammatory cells. Most evidence for the involvement of CD44 in inflammatory diseases has come from animal studies.…”

Section: Cd44 Suppresses Tlr-mediated Inflammationmentioning

confidence: 99%

“…4 This receptor is known to be involved in the binding, endocytosis, and metabolism of HA and also has additional functions in innate and adaptive immunity (1). CD44 is constitutively expressed on both hemopoietic and parenchymal cells.…”

Section: Cd44 Suppresses Tlr-mediated Inflammationmentioning

confidence: 99%

CD44 Suppresses TLR-Mediated Inflammation

Kawana

Karaki

Higashi

et al. 2008

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.

“…Abs to CD44 have been successfully used in the treatment of several animal models of autoimmune and inflammatory diseases, including experimental autoimmune encephalomyelitis (18,19), collagen-or Ab-induced arthritis (7,(20)(21)(22)(23), autoimmune diabetes (24,25), experimental autoimmune uveoretinitis (26,27), experimental colitis (28), experimental pulmonary eosinophilia (29), and cutaneous delayed-type hypersensitivity (30). The mAb rat anti-human/mouse CD44, IM7, which recognizes an extracellular epitope on the CD44s, has been extensively used in many of these studies, and robust anti-inflammatory effects have been reported with the administration of the Ab in these disease models (7,18,19,21,22,(24)(25)(26).…”

mentioning

confidence: 99%

CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcγ Receptor– and Complement Receptor 3–Dependent Mechanisms

Amash

Wang

et al. 2016

Targeting CD44, a major leukocyte adhesion molecule, using specific Abs has been shown beneficial in several models of autoimmune and inflammatory diseases. The mechanisms contributing to the anti-inflammatory effects of CD44 Abs, however, remain poorly understood. Phagocytosis is a key component of immune system function and can play a pivotal role in autoimmune states where CD44 Abs have shown to be effective. In this study, we show that the well-known anti-inflammatory CD44 Ab IM7 can inhibit murine macrophage phagocytosis of RBCs. We assessed three selected macrophage phagocytic receptor systems: Fcγ receptors (FcγRs), complement receptor 3 (CR3), and dectin-1. Treatment of macrophages with IM7 resulted in significant inhibition of FcγR-mediated phagocytosis of IgG-opsonized RBCs. The inhibition of FcγR-mediated phagocytosis was at an early stage in the phagocytic process involving both inhibition of the binding of the target RBC to the macrophages and postbinding events. This CD44 Ab also inhibited CR3-mediated phagocytosis of C3bi-opsonized RBCs, but it did not affect the phagocytosis of zymosan particles, known to be mediated by the C-type lectin dectin-1. Other CD44 Abs known to have less broad anti-inflammatory activity, including KM114, KM81, and KM201, did not inhibit FcγR-mediated phagocytosis of RBCs. Taken together, these findings demonstrate selective inhibition of FcγR and CR3-mediated phagocytosis by IM7 and suggest that this broadly anti-inflammatory CD44 Ab inhibits these selected macrophage phagocytic pathways. The understanding of the immune-regulatory effects of CD44 Abs is important in the development and optimization of therapeutic strategies for the potential treatment of autoimmune conditions.