Topical cathelicidin (LL-37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model.
BACKGROUND
Cathelicidin (LL-37) is an endogenous innate immune peptide that is elevated in patients with chronic rhinosinusitis (CRS). The role of LL-37 in olfactory epithelium (OE) inflammation remains unknown. We hypothesized that: (1) LL-37 topically delivered would elicit profound OE inflammation; and (2) LL-37 induced inflammation is associated with increased infiltration of neutrophils and mast cells.


METHODS
To test our hypothesis we challenged C57BL/6 mice intranasally with increasing concentrations of LL-37. At 24 hours tissues were examined histologically and scored for inflammatory cell infiltrate, edema, and secretory hyperplasia. In separate experiments, fluorescently conjugated LL-37 was instilled and tissues were examined at 0.5 and 24 hours. To test our last hypothesis, we performed tissue myeloperoxidase (MPO) assays for neutrophil activity and immunohistochemistry for tryptase to determine the mean number of mast cells per mm(2) .


RESULTS
LL-37 caused increased inflammatory cell infiltrate, edema, and secretory cell hyperplasia of the sinonasal mucosa, with higher LL-37 concentrations yielding significantly more inflammatory changes (p < 0.01). Fluorescent LL-37 demonstrated global sinonasal epithelial binding and tissue distribution. Further, higher concentrations of LL-37 led to significantly greater MPO levels with dose-dependent increases in mast cell infiltration (p < 0.01).


CONCLUSIONS
LL-37 has dramatic inflammatory effects in the OE mucosa that is dose-dependent. The observed inflammatory changes in the olfactory mucosa were associated with the infiltration of both neutrophils and mast cells. Our biologic model represents a new model to further investigate the role of LL-37 in OE inflammation.
Department of Surgery, Division of Head and Neck Surgery, Rhinology-Sinus and Skull Base Surgery Program, University of Utah School of Medicine, Salt Lake City, UT.|Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, UT.
Jeremiah A
JA
Alt
Department of Surgery, Division of Head and Neck Surgery, Rhinology-Sinus and Skull Base Surgery Program, University of Utah School of Medicine, Salt Lake City, UT.
Xuan
X
Qin
Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, UT.
Abigail
A
Pulsipher
Department of Surgery, Division of Head and Neck Surgery, Rhinology-Sinus and Skull Base Surgery Program, University of Utah School of Medicine, Salt Lake City, UT.
Quinn
Q
Orb
Department of Surgery, Division of Head and Neck Surgery, Rhinology-Sinus and Skull Base Surgery Program, University of Utah School of Medicine, Salt Lake City, UT.
Richard R
RR
Orlandi
Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, UT.
Jianxing
J
Zhang
Department of Surgery, Division of Pediatric Urology, University of Utah School of Medicine, Salt Lake City, UT.
Austin
A
Schults
Department of Surgery, Division of Pediatric Urology, University of Utah School of Medicine, Salt Lake City, UT.
Wanjian
W
Jia
Department of Internal Medicine, Division of Epidemiology, University of Utah, Salt Lake City, UT.
Angela P
AP
Presson
Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, UT.
Glenn D
GD
Prestwich
Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, UT.|Department of Surgery, Division of Pediatric Urology, University of Utah School of Medicine, Salt Lake City, UT.
Siam
S
Oottamasathien
D000287:Administration, Topical; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage* / Q000009:adverse effects; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009831:Olfactory Mucosa / Q000187:drug effects / Q000276:immunology*; D012220:Rhinitis / Q000188:drug therapy / Q000276:immunology*; D012852:Sinusitis / Q000188:drug therapy / Q000276:immunology*; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins
cathelicidin; chronic disease; innate immunity; rhinosinusitis; sinusitis