CD44: molecular interactions, signaling and functions in the nervous system

Dzwonek, Joanna; Wilczyński, Grzegorz M.

doi:10.3389/fncel.2015.00175

Cited by 115 publications

(102 citation statements)

References 83 publications

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“…The CD44 receptor has been described as the main receptor that modulates cell-extracellular matrix interactions (Pesarrodona et al, 2014), and is considered as the cognate receptor for hyaluronan (Bajorath et al, 1998; Teriete et al, 2004; Dzwonek and Wilczynski, 2015). It is found in several cell types, throughout the nervous system, such as glial cells (Bignami and Dahl, 1986; Gorlewicz et al, 2009; McKenzie et al, 1982) and neurons (Ailane et al, 2013; Raber et al, 2014), and in the ECM (Dzwonek and Wilczynski, 2015; Finlayson, 2015; Multhaupt et al, 2016; Murai, 2015; Orian-Rousseau and Sleeman, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…It is found in several cell types, throughout the nervous system, such as glial cells (Bignami and Dahl, 1986; Gorlewicz et al, 2009; McKenzie et al, 1982) and neurons (Ailane et al, 2013; Raber et al, 2014), and in the ECM (Dzwonek and Wilczynski, 2015; Finlayson, 2015; Multhaupt et al, 2016; Murai, 2015; Orian-Rousseau and Sleeman, 2014). Moreover, it has been shown to play a role in cell migration and activation during inflammation (Gee et al, 2004), and in neuronal development and plasticity (Kochlamazashvili et al, 2010; Wlodarczyk et al, 2011; Dzwonek and Wilczynski, 2015). Considering that it is also present on peripheral sensory neurons (Ghosh et al, 2011), the next step in our study was to test the hypothesis that hyaluronan affects nociceptor function by acting at the CD44 receptor.…”

Section: Discussionmentioning

confidence: 99%

“…All three intracellular messengers that we evaluated, PKA, PKC and Src, have also been associated to CD44 receptor signaling (Lee et al, 2008; Bourguignon et al, 2009; Bourguignon et al, 2010; Campo et al, 2010; Zhang et al, 2014). Although it has not been established how CD44 interacts with PKA, it has been shown that CD44 can directly activate PKC (Bourguignon et al, 2009; Campo et al, 2010), and members of the Src family kinases are considered crucial for CD44 signaling (Ponta et al, 2003; Skupien et al, 2014; Dzwonek and Wilczynski, 2015). To directly activate the CD44 receptor we used the peptide A6 (Piotrowicz et al, 2011; Finlayson, 2015); its administration produced robust hyperalgesia that was inhibited by both the CD44 antagonist A5G27 and HMWH, confirming the action of A6 on the CD44 receptor.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation

et al. 2016

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We propose that the extracellular matrix signals CD44, a hyaluronan receptor, to increase the responsiveness to mechanical stimulation. We report that intradermal injection of hyaluronidase induces mechanical hyperalgesia, that is inhibited by co-administration of a CD44 receptor antagonist, A5G27. The intradermal injection of low (LMWH) but not high (HMWH) molecular weight hyaluronan also induces mechanical hyperalgesia, an effect that was attenuated by the pretreatment with HMWH or A5G27. Pretreatment with HMWH also attenuated the hyperalgesia induced by hyaluronidase. Similarly, intradermal injection of A6, a CD44 receptor agonist, produced hyperalgesia that was inhibited by HMWH and A5G27. Inhibitors of protein kinase A and Src, but not protein kinase C, significantly attenuated the hyperalgesia induced by both A6 and LMWH. Finally, to determine if CD44 receptor signaling is involved in a preclinical model of inflammatory pain, we evaluated the effect of A5G27 and HMWH on the mechanical hyperalgesia associated with the inflammation induced by carrageenan. Both A5G27 and HMWH attenuated carrageenan-induced mechanical hyperalgesia. Thus, while LMWH acts at its cognate receptor, CD44, to induce mechanical hyperalgesia, HMWH acts at the same receptor as an antagonist. That the local administration of HMWH or A5G27 inhibits carrageenan-induced hyperalgesia supports the suggestion that carrageenan produces changes in the extracellular matrix that contributes to inflammatory pain. These studies define a clinically relevant role for signaling by the hyaluronan receptor, CD44, in increased responsiveness to mechanical stimulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation

et al. 2016

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“…It has been shown that astrogliosis is a major component contributing to HA deposition in EAE lesions (14,22). Reactive astrocytes produce high levels of HA, and this HA might in turn provide a feed-forward loop by signaling through CD44 on reactive astrocytes, thereby sustaining astrogliosis (43,44). We hypothesize that through this production of HA, reactive astrocytes play a role in the infiltration of pathogenic T cells into the CNS.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization

Kuipers

Rieck

Gurevich

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3+ regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS.

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“…There are multiple CD44 isoforms that arise by alternative splicing, but all forms contain the HA-binding domain within their primary sequence (Thorne et al, 2004). CD44 expression occurs in glia and some neurons, and HA-CD44 interactions are involved in glial cell differentiation and migration and in post-traumatic brain repair (Dzwonek and Wilczynski, 2015). RHAMM, the receptor for HA-mediated motility, is alternatively spliced as well, and the different forms of the resulting protein are widely found both intracellularly and on the surface of neurons and glia (Lynn et al, 2001a; Lynn et al, 2001b).…”

Section: Hyaluronanmentioning

confidence: 99%