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INFLAMMATION CYTOKINES, NEUROIMMUNE INTERACTIONS

Mast cell-dependent anorexia and hypothermia induced by mucosal activation of Toll-like receptor 7

¹Rebecca and John Moores Cancer Center, ²Department of Medicine, and ³Division of Biostatistics, University of California, San Diego, La Jolla, California

Submitted 23 July 2007 ; accepted in final form 9 May 2008

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-, and independent of IL-1β, IL-6 and cyclo-oxygenase-1 (COX1). Partial roles were also implied for mast cells and COX2. Although plasma TNF- 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- 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.

anorexia; hypothermia

This article has been cited by other articles:

				T. Hayashi, C. S. Gray, M. Chan, R. I. Tawatao, L. Ronacher, M. A. McGargill, S. K. Datta, D. A. Carson, and M. Corr Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7 PNAS, February 24, 2009; 106(8): 2764 - 2769. [Abstract] [Full Text] [PDF]