Role of ninjurin‐1 in the migration of myeloid cells to central nervous system inflammatory lesions

Ifergan, Igal; Kébir, Hania; Terouz, Simone; Alvarez, Jorge Iván; Lécuyer, Marc-André; Gendron, Steve; Bourbonnière, Lyne; Dunay, Ildikò Rita; Bouthillier, Alain; Moumdjian, Robert; Fontana, Adriano; Haqqani, Arsalan S.; Klopstein, Armelle; Prinz, Marco; López-Vales, Rubén; Birchler, Thomas; Prat, Alexandre

doi:10.1002/ana.22519

Cited by 133 publications

(139 citation statements)

References 48 publications

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“…Similar to a previous study showing that Ninj1 blockade decreased the infiltration of macrophages in an experimental model of allergic encephalomyelitis (18), targeted depletion of the Ninj1 gene significantly reduced diabetesinduced infiltration of macrophages and the generation of ROS in macrophages.…”

Section: Discussionsupporting

confidence: 86%

“…responsible for the progression of multiple sclerosis, an autoimmune inflammatory disease of the CNS characterized by demyelination and axonal damage (18). The expression of Ninj1 is significantly increased in CNS lesions of patients with multiple sclerosis, and Ninj1-neutralizing antibody suppresses neuroinflammatory responses in an experimental model of allergic encephalomyelitis that mimics multiple sclerosis (18).…”

mentioning

confidence: 99%

“…The expression of Ninj1 is significantly increased in CNS lesions of patients with multiple sclerosis, and Ninj1-neutralizing antibody suppresses neuroinflammatory responses in an experimental model of allergic encephalomyelitis that mimics multiple sclerosis (18). Moreover, Ninj1 is known to induce the regression of hyaloid blood vessels, a transiently existing vascular system involved in maturation of the lens during the embryonic period, and inhibition of Ninj1 with neutralizing antibody delays regression of the hyaloid blood vessels (19).…”

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confidence: 99%

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Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

Yin

Choi

Kim

et al. 2014

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

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Penile erection is a neurovascular phenomenon, and erectile dysfunction (ED) is caused mainly by vascular risk factors or diseases, neurologic abnormalities, and hormonal disturbances. Men with diabetic ED often have severe endothelial dysfunction and peripheral nerve damage, which result in poor response to oral phosphodiesterase-5 inhibitors. Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period. Here, we demonstrate in streptozotocin-induced diabetic mice that inhibition of the Ninj1 pathway by administering Ninj1-neutralizing antibody (Ninj1-Ab) or by using Ninj1-knockout mice successfully restored erectile function through enhanced penile angiogenesis and neural regeneration. Angiopoietin-1 (Ang1) expression was down-regulated and angiopoietin-2 expression was up-regulated in the diabetic penis compared with that in controls, and these changes were reversed by treatment with Ninj1-Ab. Ninj1 blockade-mediated penile angiogenesis and neural regeneration as well as recovery of erectile function were abolished by inhibition of Ang1-Tie2 (tyrosine kinase with Ig and epidermal growth factor homology domain-2) signaling with soluble Tie2 antibody or Ang1 siRNA. The present results suggest that inhibition of the Ninj1 pathway will be a novel therapeutic strategy for treating ED.diabetes mellitus | male sexual dysfunction | peripheral neuropathy E rectile dysfunction (ED), which is defined as an inability to attain or maintain penile erection sufficient for satisfactory sexual intercourse (1), is caused by a variety of pathologic conditions including vascular risk factors or diseases, neurologic abnormalities, and hormonal disturbances (2, 3). Diabetes mellitus is one of the most common causes of ED, and about 50-75% of male diabetic patients have ED (4, 5). Multiple pathogenetic factors, such as endothelial dysfunction, atherosclerosis, autonomic neuropathy, inflammation, fibrosis, and hypogonadism, are involved in diabetic ED (4-6). The multiple factors causing diabetic ED contribute to reduced responsiveness to currently available oral phosphodiesterase-5 (PDE5) inhibitors, which enhance the nitric oxide (NO)-cGMP pathway by inhibiting the breakdown of cGMP (7). The severity of endothelial dysfunction and peripheral neuropathy are mainly responsible for the poor responsiveness of diabetic patients to PDE5 inhibitors (8, 9). Because the effects of PDE5 inhibitors depend on endogenous NO formation, PDE5 inhibitors fail to increase the cGMP level above the threshold required for penile erection if bioavailable NO is insufficient as the result of severe endothelial dysfunction or peripheral neuropathy (9). Therefore, a new treatment strategy that corrects both endothelial dysfunction and peripheral neuropathy is required for men with diabetic ED.A variety of strategies targeting therapeutic angiogenesis and neural regeneration have been introduced to restore erectile function at the preclinical lev...

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

Yin

Choi

Kim

et al. 2014

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

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“…Ninjurin1-mediated adhesion between leukocytes and the endothelium at early stages of trafficking have been well described (17,18). Taken together with our current results, these data suggest that Ninjurin1 enhances leukocyte trafficking by performing dual stage-dependent functions, leukocyteendothelium adhesion in the early stage, and protrusive functions during diapedesis in the later stage (Fig.…”

Section: Ninjurin1 Promotes the Formation Of Adhesive And Invasive Prsupporting

confidence: 89%

Ninjurin1 Enhances the Basal Motility and Transendothelial Migration of Immune Cells by Inducing Protrusive Membrane Dynamics

Ahn¹,

Le²,

Shin³

et al. 2014

Journal of Biological Chemistry

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Background: Ninjurin1 promotes leukocyte trafficking during inflammation through homotypic binding. Results: Changes in Ninjurin1 expression in macrophages regulate protrusive membrane dynamics, motility, and in turn transendothelial migration. Conclusion:The pro-migratory function and binding activity of Ninjurin1 are important for modulating immune responses during inflammation. Significance: This study provides additional insights into the understanding of Ninjurin1-mediated inflammation.

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“…Ninj1 protein is necessary for mediating homophilic adhesion and promoting neurite outgrowth of DRG neurons (11,12), suggesting that Ninj1 plays a role in nerve regeneration. The ninj1 gene was also found to be up-regulated in myeloid cells associated with experimental allergic encephalomyelitis and active multiple sclerosis, which subsequently modulates the infiltration of inflammatory myeloid cells into central nerve system (13). Additionally, Ninj1 was found to be overexpressed in hepatocellular carcinoma (14) and acute lymphoblastic B-cell leukemia (15).…”

mentioning

confidence: 99%

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

Cho

Rossi

Jung

et al. 2013

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

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The tumor suppressor protein p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest, apoptosis, and senescence. The nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a homophilic adhesion molecule and involved in nerve regeneration. Interestingly, Ninj1 is found to be overexpressed in human cancer, but its role in tumorigenesis is not clear. Here, we found that Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage in a p53-dependent manner. We also found that knockout or knockdown of Ninj1 increases p53 expression potentially through enhanced p53 mRNA translation. In addition, we found that Ninj1 deficiency suppresses cell proliferation but enhances apoptosis and premature senescence in a p53-dependent manner. Consistent with this, we found that mice heterozygous in ninj1 are hypersensitive to ionizing radiation-induced lethality, along with increased expression of p53 in thymus. Taken together, we provided evidence that Ninj1 is a p53 target and modulates p53 mRNA translation and p53-dependent premature senescence, cell proliferation, apoptosis, and radiationinduced mortality in vitro and in vivo. Thus, we postulate that as a membrane adhesion molecule, Ninj1 is an ideal target to regulate p53 activity via the p53-Ninj1 loop. cellular senescence | radiosensitivity

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Role of ninjurin‐1 in the migration of myeloid cells to central nervous system inflammatory lesions

Abstract: Our study uncovers an important cell-specific role for Ninjurin-1 in the transmigration of inflammatory APCs across the BBB and further emphasizes the importance of myeloid cell recruitment during the development of neuroinflammatory lesions.

Cited by 133 publications

References 48 publications

Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

Ninjurin1 Enhances the Basal Motility and Transendothelial Migration of Immune Cells by Inducing Protrusive Membrane Dynamics

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

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