Nerve growth factor regulates neurolymphatic remodeling during corneal inflammation and resolution

Darci M. Fink, Alicia L. Connor, Philip M. Kelley, Maria M. Steele, Michael A Hollingsworth, Richard M Tempero

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The cellular and physiologic mechanisms that regulate the resolution of inflammation remain poorly defined despite their widespread importance in improving inflammatory disease outcomes. We studied the resolution of two cardinal signs of inflammation-pain and swelling-by investigating molecular mechanisms that regulate neural and lymphatic vessel remodeling during the resolution of corneal inflammation. A mouse model of corneal inflammation and wound recovery was developed to study this process in vivo. Administration of nerve growth factor (NGF) increased pain sensation and inhibited neural remodeling and lymphatic vessel regression processes during wound recovery. A complementary in vivo approach, the corneal micropocket assay, revealed that NGF-laden pellets stimulated lymphangiogenesis and increased protein levels of VEGF-C. Adult human dermal lymphatic endothelial cells did not express canonical NGF receptors TrkA and p75NTR or activate downstream MAPK- or Akt-pathway effectors in the presence of NGF, although NGF treatment increased their migratory and tubulogenesis capacities in vitro. Blockade of the VEGF-R2/R3 signaling pathway ablated NGF-mediated lymphangiogenesis in vivo. These findings suggest a hierarchical relationship with NGF functioning upstream of the VEGF family members, particularly VEGF-C, to stimulate lymphangiogenesis. Taken together, these studies show that NGF stimulates lymphangiogenesis and that NGF may act as a pathogenic factor that negatively regulates the normal neural and lymphatic vascular remodeling events that accompany wound recovery.

Original languageEnglish (US)
Article numbere112737
JournalPloS one
Volume9
Issue number11
DOIs
StatePublished - Nov 10 2014

Fingerprint

nerve growth factor
Nerve Growth Factor
inflammation
Lymphangiogenesis
Inflammation
vascular endothelial growth factor C
Vascular Endothelial Growth Factor C
animal injuries
Lymphatic Vessels
Recovery
Vascular Endothelial Growth Factor A
Wounds and Injuries
pain
Nerve Growth Factor Receptors
Pain
Endothelial cells
Swelling
blood vessels
Assays
endothelial cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Nerve growth factor regulates neurolymphatic remodeling during corneal inflammation and resolution. / Fink, Darci M.; Connor, Alicia L.; Kelley, Philip M.; Steele, Maria M.; Hollingsworth, Michael A; Tempero, Richard M.

In: PloS one, Vol. 9, No. 11, e112737, 10.11.2014.

Research output: Contribution to journalArticle

Fink, Darci M. ; Connor, Alicia L. ; Kelley, Philip M. ; Steele, Maria M. ; Hollingsworth, Michael A ; Tempero, Richard M. / Nerve growth factor regulates neurolymphatic remodeling during corneal inflammation and resolution. In: PloS one. 2014 ; Vol. 9, No. 11.
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