Integrins are a subclass of adhesion molecules that mediate cell–cell and cell–extracellular matrix interactions. Integrins influence transendothelial migration of lymphocytes and monocytes and are ...suitable targets for experimental immunotherapy. They are critically involved in the pathogenesis of autoimmune neuritis and abnormally expressed in human neuropathies. Also, the role of integrins in myelination, neurite outgrowth, and nerve regeneration suggests that they could be involved in the recovery phase of immune‐mediated neuropathies. We investigated by immunohistochemistry the expression of a number of integrin subunits during the course of experimental autoimmune neuritis (EAN). Results were compared with the human immune neuropathy Guillain‐Barré syndrome (GBS) and extended in vitro. Inflammation and demyelination in both EAN and GBS induced the down‐regulation of β4 integrin in Schwann cells (SCs), whereas loss of α2 was noted only in EAN. When axonal loss was present, SCs displayed α5integrin, in both EAN and GBS. In vitro, basal lamina and inflammatory cytokines modulated the expression of β4 in SCs, but they did not influence α2 and α5 expression. Finally, integrins were differentially expressed in blood vessels during EAN. In conclusion, the spatiotemporal changes in integrin expression may be used to characterize, stage, and better understand the pathogenesis and evolution of inflammation during GBS and EAN. This may help to establish useful, novel therapy for immune‐mediated neuropathies.
Integrins comprise a group of adhesion receptors involved in cell-cell and cell-extracellular matrix interactions. Evidence is accumulating that integrins expressed on mononuclear cells play a ...central role in the induction of autoimmune diseases of the central nervous system. The effects of integrins on glial cell behavior, myelination, and angiogenesis suggest that they may also have a role in resolving inflammation in the nervous system and in promoting tissue repair. We investigated the temporospatial expression of integrins in the rat central nervous system during the course of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. A higher expression of alpha v- and beta 4-integrin subunits in astrocytes and alpha 2 integrin in oligodendrocytes was observed in active lesions of experimental autoimmune encephalomyelitis, in comparison with controls. Proinflammatory cytokines, primarily TNF-alpha, also enhanced alpha v, beta 4, and alpha 2 expression in purified glial cells ex vivo. Furthermore, we observed that the expression of some integrin subunits was modulated in the cerebral vasculature during inflammation. Our results suggest an active role for glial and vascular integrins in the regulation of autoimmune diseases of the central nervous system, opening an avenue for new potential immunotherapies.
To define a role for the angiopoietin/Tie2 system in astrocytoma angiogenesis, we examined the expression of angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) in these tumors by immunohistochemistry ...and in situ hybridization. Furthermore, we studied in vitro the effects elicited by glioblastoma cell-secreted Ang1 or by recombinant Ang1 on functions of endothelial cells (ECs). Our observations of astrocytomas show that a stage-specific induction of angiopoietins occurs and is correlated with angiogenic phases of different intensity. Ang1 expression was found in a few astrocytes scattered in the tumor at all stages of astrocytoma progression. In blood vessels, Ang1 mRNA increased progressively in high-grade glioblastomas, in which the number of vessels was higher than in low-grade tumors. Ang2 was detected in tumor cells and in ECs in high-grade astrocytomas, whereas its expression was negligible in low-grade tumors. Coculture of glioblastoma cell lines producing Ang1 with endothelium demonstrated a key role of this ligand in the control of EC network organization. We found that recombinant Ang1 in vitro induces EC spreading and reorganization of the cell monolayer into cordlike structures. These results suggest that Ang1 directly acts on ECs by modulating cell-cell and cell-matrix associations and promoting the differentiation phase of angiogenesis.
Defects in laminins or laminin receptors are responsible for various neuromuscular disorders, including peripheral neuropathies. Interactions between Schwann cells and their basal lamina are ...fundamental to peripheral nerve development and successful myelination. Selected laminins are expressed in the endoneurium, and their receptors are developmentally regulated during peripheral nerve formation. Loss-of-function mutations have confirmed the importance and the role of some of these molecules. Here we show for the first time that another laminin receptor, alpha 7 beta 1 integrin, previously described only in neurons, is also expressed in Schwann cells. The expression of alpha 7 appears postnatally, such that alpha 7 beta 1 is the last laminin receptor expressed by differentiating Schwann cells. Genetic inactivation of the alpha 7 subunit in mice does not affect peripheral nerve formation or the expression of other laminin receptors. Of note, alpha 7 beta 1 is not necessary for basal lamina formation and myelination. Nonetheless, these data taken together with the previous demonstration of impaired axonal regrowth in alpha 7-null mice suggest a possible Schwann cell-autonomous role for alpha 7 in nerve regeneration.
The human 7-transmembrane receptor GPR7 has sequence similarity to opioid and somatostatin receptors, and can be activated by the recently discovered neuropeptides NPB and NPW. This receptor is ...highly expressed in the nervous system, with suggested roles in neuroendocrine events and pain signaling. In this study, we investigated whether the GPR7 receptor is expressed in the peripheral nervous system under normal and pathological conditions. A low level of GPR7 receptor was observed in myelin-forming Schwann cells in both normal human and rat nerve, and in primary rat Schwann cell cultures. Peripheral nerve samples taken from patients exhibiting inflammatory/immune-mediated neuropathies showed a dramatic increase of GPR7 receptor expression restricted to myelin-forming Schwann cells. Complementary animal models of immune-inflammatory and ligation-induced nerve injury and neuropathic pain similarly exhibited an increased myelin-associated expression of GPR7 receptor. These results suggest a relationship between the pathogenesis of inflammatory/immune-mediated neuropathies, GPR7 receptor expression, and pain transmission.
Highlights • This paper shows that DMD boys could be grouped into classes sharing trajectories. • Using analysis accounting for trajectory classes, the variation was strongly reduced. • Reducing ...unexplained variation could help to improve DMD clinical trial design.
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