Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline

Abstract

Cognitive decline following surgery in older individuals is a major clinical problem of uncertain mechanism; a similar cognitive decline also follows severe infection, chemotherapy, or trauma and is currently without effective therapy. A variety of mechanisms have been proposed, and exploring the role of inflammation, we recently reported the role of IL-1β in the hippocampus after surgery in mice with postoperative cognitive dysfunction. Here, we show that TNF-α is upstream of IL-1 and provokes its production in the brain. Peripheral blockade of TNF-α is able to limit the release of IL-1 and prevent neuroinflammation and cognitive decline in a mouse model of surgery-induced cognitive decline. TNF-α appears to synergize with MyD88, the IL-1/TLR superfamily common signaling pathway, to sustain postoperative cognitive decline. Taken together, our results suggest a unique therapeutic potential for preemptive treatment with anti-TNF antibody to prevent surgery-induced cognitive decline.

Fig. 1.

TNF-α and HMGB-1 measured by ELISA were increased following tibial surgery. (A) Plasma levels of TNF-α were significantly increased after 30 min from skin incision; (B) HMGB-1 was up-regulated after 1 h, peaking at 6 h, and returning to baseline thereafter. Plasma levels of both TNF-α (C) and HMGB-1 (D) remained at baseline following exposure to general anesthesia (2.1% isoflurane) and analgesia (buprenorphine, 1 mg/kg s.c.). Results are expressed as mean ± SEM (n = 6). *, P < 0.05; **, P < 0.001 versus naive by one-way ANOVA followed by Student-Newman-Keuls test. ND, not determined.

Fig. 2.

Effects of anti-TNF prophylaxis on systemic cytokines, neuroinflammation and cognitive behavior. (A) Systemic IL-1β and (B) IL-6 levels following anti-TNF administration 18 h preoperatively. Delayed administration (1 h) of the antibody did not provide any reduction in plasma cytokines. (C) Hippocampi were extracted 6 h after surgery. Surgery with preemptive administration of anti-TNF resulted in no changes in expression of IL-1β compared with naive mice. (D) Densitometry of microglial immunostaining with CD11b. One day after surgery, mice showed significant microgliosis compared with naive and surgical mice treated with anti-TNF. (E) Mice subjected to surgery exhibited reduced freezing to context when compared with naive mice; preoperative administration (18 h) of anti-TNF mitigated the contextual fear memory impairment. Error bars represent the means ± SEM (n = 6, n = 10 for acute behavior). *, P < 0.05; **, P < 0.01; ***, P < 0.001 by repeated measures ANOVA followed by Student-Newman-Keuls test. Kruskal-Wallis followed by the Dunn's multiple comparison test was used for categorical data. Ab, antibody; D, 1 h delayed administration of antibody; N + Ab, naive + Ab; S, surgery.

Fig. 3.

Effects of surgery-induced inflammation in MyD88^−/−. (A and B) Surgery resulted in reduced plasma levels of IL-1β and IL-6 both at 6 and 24 h, as measured by ELISA. Anti-TNF prophylaxis in MyD88^−/− reduced the amount of systemic cytokines to baseline levels. (C) Hippocampal collection was carried out 6 h after treatment. Surgery resulted in no changes in the expression of IL-1β compared with naive MyD88^−/− (KO). (D) Densitometry of microglial immunostaining showed no significant changes in microgliosis. (E) Contextual fear response is the same in MyD88^−/− animals receiving surgery compared with naive and Tlr4^−/−. Error bars represent the means ± SEM (n = 6, n = 10 for acute behavior). *, P < 0.05; **, P < 0.01 by repeated measures ANOVA followed by Student-Newman-Keuls test. Kruskal-Wallis followed by the Dunn's multiple comparison test was used for categorical data. Ab, antibody; ^−/−, MyD88^−/−; ^+/+, MyD88^+/+; ND, not determined; S, surgery.

Fig. 4.

Anti-TNF prophylaxis in Tlr4^−/−. (A) Contextual fear response is impaired in Tlr4^−/− 3 d after surgery compared with untreated. Prophylaxis with anti-TNF 18 h before surgery prevented the cognitive abnormality. (B and C) Preemptive administration of anti-TNF in Tlr4^−/− reduced the amount of systemic IL-1β and IL-6 to baseline levels, as measured by ELISA. (D) Tlr4^−/− showed signs of neuroinflammation with increased expression of hippocampal IL-1β, which was reduced by anti-TNF. (E) Densitometry of microglial immunostaining with CD11b. One day after surgery, Tlr4^−/− showed significant microgliosis compared with naive and surgical mice preoperatively treated with anti-TNF. Error bars represent the means ± SEM (n = 6, n = 10 for acute behavior). *, P < 0.05; **, P < 0.01 by one-way ANOVA followed by Student-Newman-Keuls test. Kruskal-Wallis followed by the Dunn's multiple comparison test was used for categorical data. Ab, antibody; S, surgery; ^−/−, TLR4^−/−; ^+/+, TLR4^+/+.