title: Mouse mast cell proteases 4 and 5 mediate epidermal injury through disruption of tight junctions.
abstract: We previously established a mast cell (MC)-dependent thermal injury model in mice with ulceration and scar formation that depended on nonredundant functions of mouse MC protease (mMCP)4 and mMCP5. We hypothesized that MC activation is an early event and now find by histology that exocytosis of granule contents occurred by 2 min after thermal injury in wild-type (WT) C57BL/6 mice and in the mMCP4- or mMCP5-deficient mice. The degranulation was equivalent for MCs in the dermis and hypodermis of all three strains, but only the WT mice showed an appreciable increase in epidermal thickness. There was no loss of total MCs, partially degranulated plus intact, during the 4 h of observation. By electron microscopy, MCs in all strains showed early zonal degranulation at 30 s with marked progression in magnitude by 120 s and no mitochondrial injury or cellular necrosis. Concomitantly there was an increase in intercellular spaces indicative of tight junction (TJ) disruption in WT mice but not in the mMCP4- or mMCP5-deficient strains. The desmosomes were intact in all strains. Immunodetection of the TJ protein claudin 4 in WT and mMCP5-deficient mice indicated a significant reduction after scald injury whereas mMCP4(-/-) mice showed no significant changes. Taken together, these findings reveal that a second-degree burn injury can initiate an immediate novel zonal degranulation of MCs throughout all skin layers and a disruption of the epidermal TJs dependent on the nonredundant presence of mMCP4 and mMCP5.
authors: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Lora G
authors: LG
authors: Bankova
authors: Cecilia
authors: C
authors: Lezcano
authors: Gunnar
authors: G
authors: Pejler
authors: Richard L
authors: RL
authors: Stevens
authors: George F
authors: GF
authors: Murphy
authors: K Frank
authors: KF
authors: Austen
authors: Michael F
authors: MF
authors: Gurish
mesh_terms: D000818:Animals; D002056:Burns / Q000235:genetics / Q000378:metabolism; D015550:Cell Degranulation; D053818:Chymases / Q000172:deficiency* / Q000235:genetics; D062506:Claudin-4 / Q000378:metabolism; D004817:Epidermis / Q000293:injuries / Q000378:metabolism* / Q000648:ultrastructure; D005089:Exocytosis; D005455:Fluorescent Antibody Technique; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics; D013696:Temperature; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D062506:Claudin-4; C509227:Cma1 protein, mouse; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D053818:Chymases