Netrin-1 Dampens Pulmonary Inflammation during Acute Lung Injury

Mirakaj, Valbona; Thix, Cyril A; Laucher, Stefanie; Mielke, Carina; Morote-García, Julio C.; Schmit, Marthe A.; Henes, Janek; Unertl, K.; Köhler, David; Rosenberger, Peter

doi:10.1164/rccm.200905-0717oc

Cited by 125 publications

(165 citation statements)

References 51 publications

(70 reference statements)

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“…Ly et al (26) demonstrated that the anti-inflammatory function of netrin-1 was dependent on a member of the UNC family, the UNC5b receptor in vitro through chemotactic migration studies, but they did not translate this finding into in vivo evidence. In recent studies, we demonstrated that netrin-1 dampens hypoxic inflammation through A2BAR and corroborated this during acute lung injury (12,13). In the present study, we investigated the role of netrin-1 during acute exudative inflammation and assessed its role during inflammatory peritonitis.…”

Section: A2barsupporting

confidence: 61%

“…This protein gradient possesses bifunctional potential, in that it attracts some axons to, as well as repels other axons from, the ventral midline. Subsequent studies demonstrated the expression of netrin-1 outside the nervous system within the vasculature, a reduction in netrin-1 expression during an acute inflammatory process, and that netrin-1 is a potent inhibitor of myeloid cell migration toward chemotactic stimuli in vitro (12,26). This anti-inflammatory potential of netrin-1 was corroborated by Wang et al (27) during renal ischemia-reperfusion injury.…”

Section: A2barmentioning

confidence: 86%

“…Samples were controlled for b-actin using the following primers: sense 59-GGT GGC TTT TAG GAT GGC AAG-39, antisense 59-ACT GGA ACG GTG AAG GTG ACA G-39. All PCR analyses were performed using real-time PCR (iCycler; Bio-Rad, Hercules, CA), as described previously (12).…”

Section: Transcriptional and Protein Analysismentioning

confidence: 99%

“…Only recently, neuronal-guidance proteins were identified to be part of these control mechanisms and, as such, to attenuate leukocyte infiltration and the associated cytokine release (6)(7)(8)(9)(10). The neuronal-guidance protein netrin-1 is involved in the control of local inflammation during tissue hypoxia and the early stages of acute lung injury, and its antiinflammatory function is dependent on the interaction of netrin-1 with the adenosine 2B receptor (A2BAR) (11)(12)(13). This opens the possibility of endogenous adenosine receptor activation independent of the short-lived nucleoside adenosine.…”

mentioning

confidence: 99%

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Netrin-1 Signaling Dampens Inflammatory Peritonitis

Mirakaj

Gatidou

Pötzsch

et al. 2011

The Journal of Immunology

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Previous studies implicated the anti-inflammatory potential of the adenosine 2B receptor (A2BAR). A2BAR activation is achieved through adenosine, but this is limited by its very short t1/2. To further define alternative adenosine signaling, we examined the role of netrin-1 during acute inflammatory peritonitis. In this article, we report that animals with endogenous repression of netrin-1 (Ntn1+/−) demonstrated increased cell count, increased peritoneal cytokine concentration, and pronounced histological changes compared with controls in a model of zymosan A peritonitis. Exogenous netrin-1 significantly decreased i.p. inflammatory changes. This effect was not present in animals with deletion of A2BAR (A2BAR−/−). A2BAR−/− animals demonstrated no change in cell count, i.p. cytokine concentration, or histology in response to netrin-1 injection. These data strengthen the role of netrin-1 as an immunomodulatory protein exerting its function in dependence of the A2BAR and further define alternative adenosine receptor signaling.

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Section: A2barsupporting

confidence: 61%

Section: A2barmentioning

confidence: 86%

Section: Transcriptional and Protein Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Netrin-1 Signaling Dampens Inflammatory Peritonitis

Mirakaj

Gatidou

Pötzsch

et al. 2011

The Journal of Immunology

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“…Neutrophils predominate in the lungs of patients with ALI (44) and in many animal models of ALI (45,46). A major constituent of neutrophils is the enzyme MPO (47), which is commonly used to quantify neutrophil accumulation.…”

Section: Concurrent Elevations In Lung Sp and Cox-2 Levels After Burnmentioning

confidence: 99%

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Sio

Ang

et al. 2010

The Journal of Immunology

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Acute lung injury (ALI) is a major cause of mortality in burn patients, even without direct inhalational injury. Identification of early mediators that instigate ALI after burn and of the molecular mechanisms by which they work are of high importance but remain poorly understood. We previously reported that an endogenous neuropeptide, substance P (SP), via binding neurokinin-1 receptor (NK1R), heightens remote ALI early after severe local burn. In this study, we examined the downstream signaling pathway following SP-NK1R coupling that leads to remote ALI after burn. A 30% total body surface area full-thickness burn was induced in male BALB/c wild-type (WT) mice, preprotachykinin-A (PPT-A) gene-deficient mice, which encode for SP, and PPT-A−/− mice challenged with exogenous SP. Local burn injury induced excessive SP-NK1R signaling, which activated ERK1/2 and NF-κB, leading to significant upregulation of cyclooxygenase (COX)-2, PGE metabolite, and remote ALI. Notably, lung COX-2 levels were abrogated in burn-injured WT mice by L703606, PD98059, and Bay 11-7082, which are specific NK1R, MEK-1, and NF-κB antagonists, respectively. Additionally, burn-injured PPT-A−/− mice showed suppressed lung COX-2 levels, whereas PPT-A−/− mice injected with SP showed augmented COX-2 levels postburn, and administration of PD98059 and Bay 11-7082 to burn-injured PPT-A−/− mice injected with SP abolished the COX-2 levels. Furthermore, treatment with parecoxib, a selective COX-2 inhibitor, attenuated proinflammatory cytokines, chemokines, and ALI in burn-injured WT mice and PPT-A−/− mice injected with SP. To our knowledge, we show for the first time that SP-NK1R signaling markedly elevates COX-2 activity via ERK1/2 and NF-κB, leading to remote ALI after burn.

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The plexin C1 receptor promotes acute inflammation

et al. 2014

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Acute inflammation is the pathophysiological basis of important clinical conditions associated with organ failure. The initial inflammatory response is controlled by the chemokine system, yet recent data have indicated that the neuronal guidance cues are significantly involved in the orchestration of this process. Previous work has shown the proinflammatory capacity of the guidance cue semaphorin (Sema) 7a, but the role of one of its target receptors, the plexin C1 (PLXNC1) receptor is to date unknown. We report here that PLXNC1 is expressed outside the nervous system and induced during acute inflammation.

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Netrin-1 Dampens Pulmonary Inflammation during Acute Lung Injury

Abstract: Pulmonary netrin-1 levels are repressed during ALI. This results in pronounced pulmonary damage, an increased infiltration of neutrophils, and increased pulmonary inflammation. Exogenous netrin-1 significantly dampens the extent of ALI through the adenosine 2B receptor.

Cited by 125 publications

References 51 publications

Netrin-1 Signaling Dampens Inflammatory Peritonitis

Netrin-1 Signaling Dampens Inflammatory Peritonitis

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

The plexin C1 receptor promotes acute inflammation

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