Nerve growth factor regulates neurolymphatic remodeling during corneal inflammation and resolution.
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.
University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, United States of America.
Darci M
DM
Fink
Boys Town National Research Hospital, Department of Genetics, 555 North 30th Street, Omaha, Nebraska 68131, United States of America.
Alicia L
AL
Connor
Boys Town National Research Hospital, Department of Genetics, 555 North 30th Street, Omaha, Nebraska 68131, United States of America.
Philip M
PM
Kelley
University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, United States of America.
Maria M
MM
Steele
University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, United States of America.
Michael A
MA
Hollingsworth
Boys Town National Research Hospital, Department of Genetics, 555 North 30th Street, Omaha, Nebraska 68131, United States of America; Boys Town National Research Hospital, Department of Otolaryngology, 555 North 30th Street, Omaha, Nebraska 68131, United States of America.
Richard M
RM
Tempero
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
C502240:NGF protein, human; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA