Mast cell-dependent anorexia and hypothermia induced by mucosal activation of Toll-like receptor 7.
Systemic viral infections produce a highly regulated set of responses in sickness behavior, such as fever, anorexia, and adipsia. Toll-like receptor (TLR)7, activated by viral RNA during infection, potently stimulates the innate and adaptive immune responses that aid in viral clearance. However, the physiological consequences of TLR7 activation have not been thoroughly studied. In these experiments, we used a potent synthetic TLR7 ligand, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy)adenine (SM360320; 1V136), to investigate the consequences of TLR7 activation in genetically defined strains of mice. Administration of the drug by the nasal, intragastric, or intraperitoneal routes caused transient hypophagia, hypodypsia, and hypothermia. Analyses of mutant mouse strains indicated that these effects were dependent on the expression of TLR7, its adaptor protein MyD88, and TNF-alpha, and independent of IL-1beta, IL-6 and cyclo-oxygenase-1 (COX1). Partial roles were also implied for mast cells and COX2. Although plasma TNF-alpha levels were significantly higher after systemic drug delivery, the behavioral effects were maximal when the agent was administered to the mucosa. Tissue and mucosal mast cells are known to express high levels of TLR7 and to rapidly release TNF-alpha upon TLR7 ligation. Mice deficient in tissue mast cells, W/W(v), had significantly less anorexia after TLR7 activation, and this response was restored with mast cell reconstitution. Our results thus suggest that tissue mast cells may play a role in the anorexia induced by mucosal activation of TLR7.
Hayashi
Tomoko
T
Rebecca and John Moores Cancer Center, University of California, San Diego, La Jolla, California , CA, USA.
Cottam
Howard B
HB
Chan
Michael
M
Jin
Guangyi
G
Tawatao
Rommel I
RI
Crain
Brian
B
Ronacher
Lisa
L
Messer
Karen
K
Carson
Dennis A
DA
Corr
Maripat
M
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D000855:Anorexia / Q000209:etiology*; D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004333:Drug Administration Routes; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D007035:Hypothermia / Q000209:etiology*; D008024:Ligands; D008407:Mast Cells / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*
D001067:Appetite Depressants; D016207:Cytokines; D008024:Ligands; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C508876:SM360320; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000225:Adenine