title: Mast cell-mediated inhibition of abdominal neutrophil inflammation by a PEGylated TLR7 ligand.
abstract: Although the mechanisms for sustained chemokine gradients and recurring cell infiltration in sterile peritonitis have not been elucidated, toll-like receptors (TLRs) have been implicated. To abate the deleterious recruitment of neutrophils in sterile inflammation, we repeatedly administered a TLR7 ligand that hyposensitized to TLR7 and receptors that converged on the MyD88-signaling intermediary and reduced cellular infiltration in murine autoimmune models of multiple sclerosis and arthritis. To reduce potential adverse effects, a polyethylene glycol polymer was covalently attached to the parent compound (Tolerimod1). The proinflammatory potency of Tolerimod1 was 10-fold less than the unconjugated TLR7 ligand, and Tolerimod1 reduced neutrophil recruitment in chemically induced peritonitis and colitis. The effects of Tolerimod1 were mediated by the radioresistant cells in radiation chimeric mice and by mast cells in reconstituted mast cell-deficient mice (Kit(W-sh)). Although the Tolerimod1 had weak proinflammatory agonist activity, it effectively reduced neutrophil recruitment in sterile peritoneal inflammation.
authors.affiliation: Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, San Diego, CA 92093-0820, USA. thayashi@ucsd.edu
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.forename: Shiyin
authors.initials: S
authors.lastname: Yao
authors.forename: Brian
authors.initials: B
authors.lastname: Crain
authors.forename: Michael
authors.initials: M
authors.lastname: Chan
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
authors.forename: Fitzgerald
authors.initials: F
authors.lastname: Lao
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002460:Cell Line; D007249:Inflammation / Q000188:drug therapy; D008024:Ligands; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D011092:Polyethylene Glycols / Q000378:metabolism* / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry; D011687:Purines / Q000494:pharmacology*; D019089:Stem Cell Factor / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D008024:Ligands; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011108:Polymers; D011687:Purines; D019089:Stem Cell Factor; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D011092:Polyethylene Glycols; D009195:Peroxidase