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

Section of Cardiovascular Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2008; 180(4):2625-33. DOI: 10.4049/jimmunol.180.4.2625
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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 CD44(null) infarcts, the enhanced inflammatory phase was followed by decreased fibroblast infiltration, reduced collagen deposition, and diminished proliferative activity. Isolated CD44(null) cardiac fibroblasts had reduced proliferation upon stimulation with serum and decreased collagen synthesis in response to TGF-beta 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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Available from: Sandra B Haudek, Oct 04, 2015
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    • "In addition, they demonstrated decreased levels of a-SMA in CD44- deficient fibroblasts compared with wild-type fibroblasts, suggesting that the presence of CD44 may affect fibroblast activation. In vivo studies demonstrated that CD44-deficient mice had significantly lower a-SMA-positive myofibroblast density and reduced collagen content in the infarcted myocardium (Huebener et al. 2008), and in the obstructed kidney (Pouschop et al. 2004) compared with wild-type mice. Collectively, these data suggest a role for CD44 in mediating myofibroblast invasion and subsequent tissue fibrosis in PVR. "
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    ABSTRACT: Fibrotic disorders are associated with activation of fibroblasts into extracellular matrix-secreting myofibroblasts expressing α-smooth muscle actin (α-SMA). Myofibroblasts are the predominant cellular component of proliferative vitreoretinopathy (PVR) epiretinal membranes. We investigated the expression of molecules involved in myofibroblast activation, migration and proliferation in PVR epiretinal membranes. Fifteen membranes were studied by immunohistochemical techniques using monoclonal and polyclonal antibodies directed against snail, fibroblast activation protein (FAP), CD44, hydrogen peroxide-inducible clone-5 (Hic-5), galectin-3, interleukin-13 receptor α2 (IL-13Rα2) and receptor for advanced glycation end products (RAGE). Myofibroblasts expressing α-SMA were present in all membranes. Myofibroblasts expressed nuclear immunoreactivity for Snail and Hic-5, cytoplasmic immunoreactivity for FAP, IL-13Rα2 and RAGE and membranous immunoreactivity for CD44. There was no immunoreactivity for galectin-3. The number of cells expressing α-SMA correlated significantly with the number of cells expressing Snail (r = 0.56; p = 0.03), Hic-5 (r = 0.526; p = 0.044), IL-13Rα2 (r = 0.773; p = 0.001) and RAGE (r = 0.734; p = 0.002). Snail, FAP, CD44, Hic-5, IL13Rα2 and RAGE may be involved in proliferative events occurring in PVR.
    Acta ophthalmologica 03/2011; 89(2):e115-21. DOI:10.1111/j.1755-3768.2010.01916.x · 2.84 Impact Factor
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    • "For example, studies with knockout mice lacking HA-binding receptors, such as CD44 and RHAMM (receptor for hyaluronan-mediated motility) or Toll-like receptors 2 and 4, might illuminate the mechanism by which injected HA is retained in or near the joint space. Thus binding of exogenously delivered HA to such receptors might abrogate cell stress responses to joint injury, processes which might otherwise result in inflammation, cytokine release and accelerated tissue destruction [30-32]. "
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    ABSTRACT: Intraarticular hyaluronan (HA) is used clinically for symptomatic relief in patients with knee osteoarthritis (OA); however, the mechanism of action is unclear. In this study, we examined the effects of a single injection of HA on joint tissue pathology, mechanical allodynia and gait changes (measured by stride times) in a murine model of OA. OA was induced in the right knee joint (stifle) of 12-week-old male C57BL/6 mice by transforming growth factor β1 (TGFβ1) injection and treadmill running for 14 days. Gait parameters were quantified by using TreadScan, mechanical allodynia was evaluated with von Frey filaments, and joint pathology was evaluated by scoring of macroscopic images for both cartilage erosion and periarticular fibrosis. HA or saline control was injected 1 day after TGFβ1 injection but before the start of treadmill running. OA development in this model was accompanied by significant (P < 0.01) enhancement of the stance and propulsion times of affected legs. HA injection (but not saline injection) blocked all gait changes and also protected joints from femoral cartilage erosion as well as tibial and femoral tissue fibrosis. Both HA injection and saline injection attenuated acute allodynia, but the HA effect was more pronounced and prolonged than the saline injection. We conclude that videographic gait analysis is an objective, sensitive and reproducible means of monitoring joint pathology in experimental murine OA, since stance time appears to correlate directly with OA severity. A single injection of HA prevents acute and prolonged gait changes and ameliorates the cartilage erosion and periarticular fibrosis normally seen in this model. We speculate that the capacity of HA to prevent cartilage erosion results from its normalization of joint biomechanics and its inhibitory effects on periarticular cells, which are involved in tissue hyperplasia and fibrosis. This effect of exogenous HA appears to mimic the protective effects of ablation of Adamts5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) on experimental murine OA, and we speculate that a common mechanism is involved.
    Arthritis research & therapy 03/2011; 13(2):R46. DOI:10.1186/ar3286 · 3.75 Impact Factor
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    • "Hyaluronan also increases during inflammatory conditions such as sarcoidosis, idiopathic pulmonary fibrosis, and bleomycin-induced lung injury models. The hyaluronan receptor, CD44, regulates both the inflammatory and fibrotic responses to MI (Huebener, et al. 2008). Together, these studies indicate that hyaluronan may serve to increase tissue edema and increase presentation of ligands for inflammatory cell receptors (Gerdin and Hallgren 1997, Waldenstrom, et al. 1991). "
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    ABSTRACT: The cardiac extracellular matrix (ECM) provides a platform for cells to maintain structure and function, which in turn maintains tissue function. In response to injury, the ECM undergoes remodeling that involves synthesis, incorporation, and degradation of matrix proteins, with the net outcome determined by the balance of these processes. The major goals of this review are a) to serve as an initial resource for students and investigators new to the cardiac ECM remodeling field, and b) to highlight a few of the key exciting avenues and methodologies that have recently been explored. While we focus on cardiac injury and responses of the left ventricle (LV), the mechanisms reviewed here have pathways in common with other wound healing models.
    Life sciences 09/2010; 87(13-14):391-400. DOI:10.1016/j.lfs.2010.07.010 · 2.70 Impact Factor
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