title: Neurogenic factor-induced Langerhans cell activation in diabetic mice with mechanical allodynia.
abstract: BACKGROUND
  Langerhans cells (LCs) are antigen-presenting dendritic cells located in the skin. It has been reported that LC activation is associated with painful diabetic neuropathy (PDN); however, the mechanism of LC activation is still unclear.
  
  
  METHODS
  The db/db mouse, a rodent model of PDN, was used to study the roles of LCs in the development of PDN in type 2 diabetes. Hind foot pads from db/db and control db/+ mice from 5 to 24 weeks of age (encompassing the period of mechanical allodynia development and its abatement) were collected and processed for immunohistochemistry studies. LCs were identified with immunohistochemistry using an antibody against CD207 (Langerin). The intraepidermal nerve fibers and subepidermal nerve plexus were identified by immunohistochemistry of protein gene product 9.5 (PGP 9.5) and tropomyosin-receptor kinase (Trk) A, the high affinity nerve growth factor receptor.
  
  
  RESULTS
  CD207-positive LCs increased in the db/db mouse during the period of mechanical allodynia, from 8 to 10 weeks of age, in both the epidermis and subepidermal plexus. At 16 weeks of age, when mechanical allodynia diminishes, LC populations were reduced in the epidermis and subepidermal plexus. Epidermal LCs (ELCs) were positive for Trk A. Subepidermal LCs (SLCs) were positive for CD68, suggesting that they are immature LCs. Additionally, these SLCs were positive for the receptor of advanced glycation end products (RAGE) and were in direct contact with TNF-α-positive nerve fibers in the subepidermal nerve plexus during the period of mechanical allodynia. Intrathecal administration of SB203580, a p38 kinase inhibitor, significantly reduced mechanical allodynia, TNF-α expression in the subepidermal plexus, and increased both ELC and SLC populations during the period of mechanical allodynia.
  
  
  CONCLUSIONS
  Our data support the hypothesis that increased LC populations in PDN are activated by p38-dependent neurogenic factors and may be involved in the pathogenesis of PDN.
authors.affiliation: Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Dauch
authors.forename: Diane E
authors.initials: DE
authors.lastname: Bender
authors.forename: Lucía A
authors.initials: LA
authors.lastname: Luna-Wong
authors.forename: Wilson
authors.initials: W
authors.lastname: Hsieh
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Yanik
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Kelly
authors.forename: Hsinlin T
authors.initials: HT
authors.lastname: Cheng
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000954:Antigens, Surface / Q000378:metabolism; D018968:CD58 Antigens / Q000378:metabolism; D003627:Data Interpretation, Statistical; D003929:Diabetic Neuropathies / Q000473:pathology*; D006930:Hyperalgesia / Q000473:pathology*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007801:Langerhans Cells / Q000187:drug effects*; D037181:Lectins, C-Type / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D020917:Receptor, trkA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000954:Antigens, Surface; D018968:CD58 Antigens; C498497:Cd207 protein, mouse; D007093:Imidazoles; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D009414:Nerve Growth Factors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D020917:Receptor, trkA; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580