Toll-like receptor 3 dynamics in female C57BL/6J mice: Regulation of alcohol intake

• Published in: Brain, behavior, and immunity behavior, and immunity, 2019-03, Vol.77, p.66-76
• Main Authors: Warden, Anna S., Azzam, Moatasem, DaCosta, Adriana, Mason, Sonia, Blednov, Yuri A., Messing, Robert O., Mayfield, R. Dayne, Harris, R. Adron
• Format: Article
• Language: English
• Subjects: Alcohol; Alcohol Drinking - immunology; Alcohol Drinking - metabolism; Alcohol use disorder; Animals; Cytokines; Cytokines - metabolism; Drinking; Ethanol - administration & dosage; Female; Females; Immunity, Innate - drug effects; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88 - metabolism; Neuroimmune; Poly I-C - pharmacology; Poly(I:C); Sex; Sex Factors; Signal Transduction - drug effects; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 4 - metabolism; Toll-like receptors
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2018.12.006

•Females have a delayed and prolonged proinflammatory response after poly(I:C).•Timecourse of cytokine activation regulated alcohol intake in both sexes.•Increased TRIF-dependent signaling enables escalation of alcohol intake.•Decreased MyD88-dependent signaling enables suppression of alcohol intake.•Decreased alcohol intake due to poly(I:C) is dependent on MyD88 in females. Although there are sex differences in the effects of alcohol on immune responses, it is unclear if sex differences in immune response can influence drinking behavior. Activation of toll-like receptor 3 (TLR3) by polyinosinic:polycytidylic acid (poly(I:C)) produced a rapid proinflammatory response in males that increased alcohol intake over time (Warden et al., 2019). Poly(I:C) produced a delayed and prolonged innate immune response in females. We hypothesized that the timecourse of innate immune activation could regulate drinking behavior in females. Therefore, we chose to test the effect of two time points in the innate immune activation timecourse on every-other-day two-bottle-choice drinking: (1) peak activation; (2) descending limb of activation. Poly(I:C) reduced ethanol consumption when alcohol access occurred during peak activation. Poly(I:C) did not change ethanol consumption when alcohol access occurred on the descending limb of activation. Decreased levels of MyD88-dependent pathway correlated with decreased alcohol intake and increased levels of TRIF-dependent pathway correlated with increased alcohol intake in females. To validate the effects of poly(I:C) were mediated through MyD88, we tested female mice lacking Myd88. Poly(I:C) did not change alcohol intake in Myd88 knockouts, indicating that poly(I:C)-induced changes in alcohol intake are dependent on MyD88 in females. We next determined if the innate immune timecourse also regulated drinking behavior in males. Poly(I:C) reduced ethanol consumption in males when alcohol was presented at peak activation. Therefore, the timecourse of innate immune activation regulates drinking behavior and sex-specific dynamics of innate immune response must be considered when designing therapeutics to treat excessive drinking.