The Axonal Guidance Receptor Neogenin Promotes Acute Inflammation

König, Klemens; Gatidou, Dimitra; Granja, Tiago; Meier, Jens; Rosenberger, Peter; Mirakaj, Valbona

doi:10.1371/journal.pone.0032145

Cited by 19 publications

(15 citation statements)

References 32 publications

(36 reference statements)

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“…For example, inflammation is reduced in neogenin knockout mice in models of peritonitis, lung injury and ischemia-reperfusion. Thus, contrary to its reported anti-inflammatory effects, these findings support the interpretation that Netrin-1 has pro-inflammatory properties via interactions with distinct neogenin-expressing leukocyte subsets (25–27). Our new findings in this report indicate that the key function of Netrin-1 on CD4+ T lymphocytes is to induce chemokinesis, and that its effect on either chemoattraction or chemorepulsion are a function of random directional migration and/or additional factors.…”

Section: Discussionsupporting

confidence: 75%

“…This effect was reported to be mediated in part via its effects on the local infiltration of neutrophils and macrophages (16, 18, 20, 34). However, more recent studies indicate that the expression of pro-migratory neogenin may be critical in the functional outcome of an inflammatory response (25–27, 35, 36). For example, inflammation is reduced in neogenin knockout mice in models of peritonitis, lung injury and ischemia-reperfusion.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in an atherosclerosis model, Netrin-1 was found to retain macrophages within plaques by inhibiting macrophage emigration from the inflammatory site (5); also Netrin-1 has been found to promote chronic inflammation in adipose tissue (24). Several studies have evaluated Netrin-1 receptor biology using neogenin knockout mice which mount a reduced inflammatory peritonitis reaction (25), have less leukocyte infiltrates and reduced inflammation in models of acute lung injury (26) and ischemia reperfusion injury (27). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Netrin-1 Augments Chemokinesis in CD4+ T Cells In Vitro and Elicits a Proinflammatory Response In Vivo

Boneschansker

Nakayama

Eisenga

et al. 2016

The Journal of Immunology

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Netrin-1 is a neuronal guidance cue that regulates cellular activation, migration and cytoskeleton rearrangement in multiple cell types. It is a chemotropic protein that is expressed in multiple tissues and elicits both attractive and repulsive migratory responses. Netrin-1 has recently been found to modulate the immune response via the inhibition of neutrophil and macrophage migration. However, the ability of Netrin-1 to interact with lymphocytes, and its in-depth effects on leukocyte migration is poorly understood. Here, we profiled the mRNA and protein expression of known Netrin-1 receptors on human CD4+ T-cells. Neogenin, UNC5A and UNC5B were expressed at low levels in unstimulated cells, but increased following mitogen-dependent activation. By immunofluorescence, we observed a cytoplasmic staining pattern of neogenin and UNC5A-B that also increased following activation. Using a novel microfluidic assay, we found that Netrin-1 stimulated bi-directional migration and enhanced the size of migratory subpopulations of mitogen-activated CD4+ T-cells, but it had no demonstrable effects on the migration of purified CD4+CD25+CD127dim T regulatory cells. Furthermore, using a shRNA knockdown approach, we observed that the pro-migratory effects of Netrin-1 on T effectors is dependent on its interactions with neogenin. In the humanized SCID mouse, local injection of Netrin-1 into skin enhanced inflammation and the number of neogenin-expressing CD3+ T cell infiltrates. Neogenin was also observed on CD3+ T cell infiltrates within human cardiac allograft biopsies with evidence of rejection. Collectively, our findings demonstrate that Netrin-1/neogenin interactions augment CD4+ T cell chemokinesis and promote cellular infiltration in association with acute inflammation in vivo.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Netrin-1 Augments Chemokinesis in CD4+ T Cells In Vitro and Elicits a Proinflammatory Response In Vivo

Boneschansker

Nakayama

Eisenga

et al. 2016

The Journal of Immunology

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“…However, it was not demonstrated that the formation of this complex was dependent on WIP phosphorylation by PKCθ (Krzewski et al, 2006). Interestingly, it has been recently published the kinome of NK cells activated by CD16 or simultaneous CD244 and DNAM-1 ligation, being PKC-θ identified as the only PKC isoform that increase phosphorylation upon receptor ligation (König et al, 2012). …”

Section: A Role For Pkcθ In Nk Cell Degranulation?mentioning

confidence: 99%

Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity

Anel¹,

Aguilo²,

Catalán³

et al. 2012

Front. Immun.

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The protein kinase C-θ (PKCθ), which is essential for T cell function and survival, is also required for efficient anti-tumor immune surveillance. Natural killer (NK) cells, which express PKCθ, play a prominent role in this process, mainly by elimination of tumor cells with reduced or absent major histocompatibility complex class-I (MHC-I) expression. This justifies the increased interest of the use of activated NK cells in anti-tumor immunotherapy in the clinic. The in vivo development of MHC-I-deficient tumors is much favored in PKCθ−/− mice compared with wild-type mice. Recent data offer some clues on the mechanism that could explain the important role of PKCθ in NK cell-mediated anti-tumor immune surveillance: some studies show that PKCθ is implicated in signal transduction and anti-tumoral activity of NK cells elicited by interleukin (IL)-12 or IL-15, while others show that it is implicated in NK cell functional activation mediated by certain killer-activating receptors. Alternatively, the possibility that PKCθ is involved in NK cell degranulation is discussed, since recent data indicate that it is implicated in microtubule-organizing center polarization to the immune synapse in CD4+ T cells. The implication of PKC isoforms in degranulation has been more extensively studied in cytotoxic T lymphocyte, and these studies will be also summarized.

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“…The receptor of Netrin-1 and RGM-A, Neogenin 1 (Neo1), plays an important role during the onset of acute inflammation. [51][52][53] A recent report identified a previously unknown role of Neo1 during the resolution of inflammation and during regeneration. 54 Functional inhibition of Neo1 stimulated the apoptosis of human PMNs and activated find-me signals on apoptotic PMNs as well as findme and eat-me receptors on human MΦs.…”

Section: Impact Of Neogenin On Inflammation Resolution and Tissue Regmentioning

confidence: 99%

<p>Novel Resolution Mediators of Severe Systemic Inflammation</p>

Gudernatsch¹,

Stefanczyk²,

Mirakaj³

2020

ITT

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Nonresolving inflammation, a hallmark of underlying severe inflammatory processes such as sepsis, acute respiratory distress syndrome and multiple organ failure is a major cause of admission to the intensive care unit and high mortality rates. Many survivors develop new functional limitations and health problems, and in cases of sepsis, approximately 40% of patients are rehospitalized within three months. Over the last few decades, better treatment approaches have been adopted. Nevertheless, the lack of knowledge underlying the complex pathophysiology of the inflammatory response organized by numerous mediators and the induction of complex networks impede curative therapy. Thus, increasing evidence indicates that resolution of an acute inflammatory response, considered an active process, is the ideal outcome that leads to tissue restoration and organ function. Many mediators have been identified as immunoresolvents, but only a few have been shown to contribute to both the initial and resolution phases of severe systemic inflammation, and these agents might finally substantially impact the therapeutic approach to severe inflammatory processes. In this review, we depict different resolution mediators/immunoresolvents contributing to resolution programmes specifically related to life-threatening severe inflammatory processes.

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The Axonal Guidance Receptor Neogenin Promotes Acute Inflammation

Cited by 19 publications

References 32 publications

Netrin-1 Augments Chemokinesis in CD4+ T Cells In Vitro and Elicits a Proinflammatory Response In Vivo

Netrin-1 Augments Chemokinesis in CD4+ T Cells In Vitro and Elicits a Proinflammatory Response In Vivo

Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity

<p>Novel Resolution Mediators of Severe Systemic Inflammation</p>

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