Inhibition of neogenin fosters resolution of inflammation and tissue regeneration
Martin Schlegel, … , Martin Giera, Valbona Mirakaj
Martin Schlegel, … , Martin Giera, Valbona Mirakaj
Published September 17, 2018
Citation Information: J Clin Invest. 2018;128(10):4711-4726. https://doi.org/10.1172/JCI96259.
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Research Article Immunology Inflammation

Inhibition of neogenin fosters resolution of inflammation and tissue regeneration

Abstract

The resolution of inflammation is an active process that is coordinated by endogenous mediators. Previous studies have demonstrated the immunomodulatory properties of the axonal guidance proteins in the initial phase of acute inflammation. We hypothesized that the neuronal guidance protein neogenin (Neo1) modulates mechanisms of inflammation resolution. In murine peritonitis, Neo1 deficiency (Neo1–/–) resulted in higher efficacies in reducing neutrophil migration into injury sites, increasing neutrophil apoptosis, actuating PMN phagocytosis, and increasing the endogenous biosynthesis of specialized proresolving mediators, such as lipoxin A4, maresin-1, and protectin DX. Neo1 expression was limited to Neo1-expressing Ly6Chi monocytes, and Neo1 deficiency induced monocyte polarization toward an antiinflammatory and proresolving phenotype. Signaling network analysis revealed that Neo1–/– monocytes mediate their immunomodulatory effects specifically by activating the PI3K/AKT pathway and suppressing the TGF-β pathway. In a cohort of 59 critically ill, intensive care unit (ICU) pediatric patients, we found a strong correlation between Neo1 blood plasma levels and abdominal compartment syndrome, Pediatric Risk of Mortality III (PRISM-III) score, and ICU length of stay and mortality. Together, these findings identify a crucial role for Neo1 in regulating tissue regeneration and resolution of inflammation, and determined Neo1 to be a predictor of morbidity and mortality in critically ill children affected by clinical inflammation.

Authors

Martin Schlegel, Andreas Körner, Torsten Kaussen, Urs Knausberg, Carmen Gerber, Georg Hansmann, Hulda Soffia Jónasdóttir, Martin Giera, Valbona Mirakaj

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Figure 8

Exogenous inhibition of Neo1 attenuates inflammation and fosters resolution programs.

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Exogenous inhibition of Neo1 attenuates inflammation and fosters resolut...
WT mice were challenged with ZyA and subsequently injected with either IgG or a Neo1 inhibitory Ab, and lavages were collected at 4, 12, 24, and 48 hours. (A) The total leukocytes were enumerated by light microscopy, and the PMNs were determined by flow cytometry. (B) The resolution index was calculated as previously described (41). (C) Classical, nonclassical, peritoneal MΦ, and monocyte-derived MΦ efferocytosis were assessed by flow cytometry. (D) Proinflammatory cytokines TNF-α, IL-1β, IL-6, and KC 4 hours after ZyA injection. The therapeutic potential of Neo1 blockade was evaluated by application of anti-Neo1 Ab 4 hours after ZyA peritonitis induction at the peak of inflammation and peritoneal lavages were collected at 12, 24, and 48 hours. Results represent at least 2 independent experiments and are expressed as mean ± SEM (A, C) and median ± 95% CI (D) (n = 8–12 per group). Statistical analysis was done by unpaired Student’s t test *P < 0.05; **P < 0.01; ***P < 0.001.