Netrin-1 Signaling Dampens Inflammatory Peritonitis

Mirakaj, Valbona; Gatidou, Dimitra; Pötzsch, Claudia; König, Klemens; Rosenberger, Peter

doi:10.4049/jimmunol.1002671

Cited by 70 publications

(81 citation statements)

References 36 publications

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“…Previous work also suggested that the administration of netrin 1 inhibits inflammation in several models of animal disease (36,37), but in our CIA mice, an anti-inflammatory effect of netrin 1 was not detected. Indeed, netrin 1 may not always exhibit anti-inflammatory activity, and contradictory results have been reported.…”

Section: Role Of Netrin 1 In Bone Homeostasiscontrasting

confidence: 84%

Bone-protective Functions of Netrin 1 Protein

Maruyama

Kawasaki

Hamaguchi³

et al. 2016

Journal of Biological Chemistry

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Edited by Amanda FosangNetrin 1 was initially identified as an axon guidance factor, and recent studies indicate that it inhibits chemokine-directed monocyte migration. Despite its importance as a neuroimmune guidance cue, the role of netrin 1 in osteoclasts is largely unknown. Here we detected high netrin 1 levels in the synovial fluid of rheumatoid arthritis patients. Netrin 1 is potently expressed in osteoblasts and synovial fibroblasts, and IL-17 robustly enhances netrin 1 expression in these cells. The binding of netrin 1 to its receptor UNC5b on osteoclasts resulted in activation of SHP1, which inhibited VAV3 phosphorylation and RAC1 activation. This significantly impaired the actin polymerization and fusion, but not the differentiation of osteoclast. Strikingly, netrin 1 treatment prevented bone erosion in an autoimmune arthritis model and age-related bone destruction. Therefore, the netrin 1-UNC5b axis is a novel therapeutic target for bone-destructive diseases.

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Section: Role Of Netrin 1 In Bone Homeostasiscontrasting

confidence: 84%

Bone-protective Functions of Netrin 1 Protein

Maruyama

Kawasaki

Hamaguchi³

et al. 2016

Journal of Biological Chemistry

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“…Such bidirectional communication involves cytokine-induced neurological responses (16,17), as well as the modulation of the immune response by neurotransmitters and neuronal guidance proteins (4,5,18). Interestingly, whereas in the former case both protective and deteriorative neurologic responses may be triggered by immune-related compounds (15), in the latter there is a preserved correlation of NGPs serving as a stop signal both for axonal migration and for migration of leukocytes, as demonstrated for netrin-1 and RGM-A (4)(5)(6)19). In other words, to date there was only evidence of a protective immune response for NGPs during hypoxia and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Semaphorin 7A promotes neutrophil migration during hypoxia

Morote-García

Napiwotzky

Köhler

et al. 2012

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

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Recent studies identified basic biological principles that are shared by the immune and the nervous system. One of these analogies applies to the orchestration of cellular migration where guidance proteins that serve as a stop signal for axonal migration can also serve as a stop signal for the migration of immune-competent cells. The control of leukocyte migration is of key interest during conditions associated with inflammatory tissue changes such as tissue hypoxia or hypoxic inflammation. Semaphorins are members of these axon guidance molecules. Previously unknown, we report here the expression and induction of semaphorin 7A (SEMA7A) on endothelium through hypoxia-inducible factor 1α during hypoxia. This induction of SEMA7A translates into increased transmigration of polymorphonuclear neutrophil granulocytes across endothelial cells. Extension of these findings demonstrated an attenuated extravasation of polymorphonuclear neutrophil granulocytes in Sema7a-deficient mice from the vasculature during hypoxia. Studies using chimeric animals identified the expression of Sema7A on nonhematopoietic tissue to be the underlying cause of the observed results. Taken together, our findings demonstrate that neuronal guidance proteins do not only serve as a stop signal for leukocyte migration but also can propagate the extravasation of leukocytes from the vascular space. Future antiinflammatory strategies might be based on this finding. endothelia | inflammation R ecent years have identified a close link between hypoxia and inflammation (1). Similar to an acute inflammatory response, hypoxia is marked by increased paracellular fluid exchange and the extravasation of immune-competent cells from the vascular space. Likewise, limited oxygen availability might be the product of the characteristic metabolic changes of inflammation leading to inflammation-associated hypoxia. In addition, proinflammatory cytokines that are released upon stimulation of the immune system might also be part of the hypoxia-enhanced expression of the transcription factor NF-κB (2). Neuronal guidance proteins (NGPs) notably mitigate the course of this process (3-5). For example, cues initially reported to guide neuronal growth and migration, such as netrin-1 or the repulsive guidance molecule (RGM)-A, reduce inflammatory tissue changes (4-6).A member of these NGPs are the semaphorins, a large family of secreted and cell-surface proteins recently found to modulate neurite extension. A member of this family, Semaphorin 7A (SEMA7A), holds the ability to induce the production of cytokines in macrophages and monocytes, which play a significant role during the effector phase of the inflammatory immune response (7,8). Furthermore, SEMA7A also stimulates cytoskeletal reorganization in melanocytes and monocytes, which translates into cell morphology changes that can result in spreading and migration of these types of cells (9-11). However, to date, the role and expression of SEMA7A during hypoxia was unknown.On the basis of these observations, we examined the in...

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“…Previous studies have shown netrin-1 to have anti-inflammatory functions in several conditions, including acute kidney injury, acute experimental colitis, corneal injury, peritonitis, and acute lung injury. 29,33e40 Although the mechanism by which netrin-1 regulates inflammation remains largely unknown, roles in inhibiting immune cell infiltration 34,36,38,39,41 and macrophage polarization 35 and reducing the levels of proinflammatory cytokines and chemokines 29,42 have been reported. On the other hand, netrin-1 has also been shown to be proinflammatory in atherosclerotic plaques, where it inhibits emigration of macrophages from the lesions and promotes macrophage survival.…”

Section: Discussionmentioning

confidence: 99%

Full-Length and Fragmented Netrin-1 in Multiple Sclerosis Plaques Are Inhibitors of Oligodendrocyte Precursor Cell Migration

Bin

Rajasekharan

Kuhlmann

et al. 2013

The American Journal of Pathology

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Oligodendrocytes exhibit a limited capacity to remyelinate in multiple sclerosis. Factors present in multiple sclerosis lesions are thought to inhibit oligodendrocyte precursor cell migration, limiting their recruitment to axons requiring remyelination; however, few inhibitors have been identified. A candidate inhibitor is netrin-1, a secreted protein that repels migrating oligodendrocyte precursor cells during neural development and is expressed by myelinating oligodendrocytes in the mature rodent central nervous system. Herein, we examined the distribution of netrin-1 in adult human white matter and multiple sclerosis lesions. We detected full-length netrin-1 protein and shorter netrin-1 fragments in samples of normal white matter and of multiple sclerosis lesions from adult human brain. We demonstrate that peptides corresponding to amino terminal domains VI and V of netrin-1 repel migrating oligodendrocyte precursor cells, but lack the chemoattractant activity of full-length netrin-1. Furthermore, recombinant domains VI-V of netrin-1 disrupt the chemoattractant activity of full-length netrin-1, consistent with a competitive mechanism of action. These findings indicate that full-length and fragmented forms of netrin-1, found in multiple sclerosis lesions, have the capacity to inhibit oligodendrocyte precursor migration, identifying netrin-1 as a potential target for therapies that promote remyelination.

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Netrin-1 Signaling Dampens Inflammatory Peritonitis

Cited by 70 publications

References 36 publications

Bone-protective Functions of Netrin 1 Protein

Bone-protective Functions of Netrin 1 Protein

Endothelial Semaphorin 7A promotes neutrophil migration during hypoxia

Full-Length and Fragmented Netrin-1 in Multiple Sclerosis Plaques Are Inhibitors of Oligodendrocyte Precursor Cell Migration

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