Systemic Interleukin‐1β Elicits Cyclooxygenase‐Independent Fever

Field: Neuroscience (Life Sciences)

Interleukin‐1β (IL‐1β) induces neuroimmune responses that help to fight infections. IL‐1β‐induced fever is not abolished by cyclooxygenase (COX) inhibitors used to treat inflammation and the neural pathways responsible for COX‐independent fever are still unknown. Considering that neurons that reside in the rostral raphe pallidus area (rRPa) and in the dorsomedial hypothalamus (DMH) play a key role in the control of thermoeffectors, we hypothesized that neurons in these areas contribute to COX‐independent fever elicited by intravenous (iv) IL‐1β. Female and male Sprague Dawley rats were anesthetized with urethane and α‐chloralose (ur/ch) or isoflurane (iso) and treated with saline or indomethacin, prior to receiving iv IL‐1β. Systemic IL‐1β increased brown adipose tissue (BAT) sympathetic nerve activity (SNA) (+2852 ± 2020% baseline (BL), p = 0.003), BAT temperature (TBAT; +2.6 ± 1.3°C, p < 0.001), expired CO2 (+1.0 ± 0.4%, p < 0.001), core body temperature (TCORE; +0.6 ± 0.2°C, p < 0.001), heart rate (HR; +102 ± 42 bpm, p < 0.001), mean arterial pressure (MAP; +11 ± 7 mmHg, p = 0.002), and paw temperature (TPAW; ‐6.9 ± 1.2°C, p < 0.001), which is an index of cutaneous vasoconstriction (CVC). Indomethacin did not prevent IL‐1β‐evoked increases in BAT SNA (+2545 ± 756% BL, p < 0.001), TBAT (+2.9 ± 1.3°C, p < 0.001), expired CO2 (+1.2 ± 0.6%, p = 0.003), TCORE (+0.9 ± 0.5°C, p = 0.005), HR (+117 ± 47 bpm, p < 0.001), MAP (+27 ± 20 mmHg, p = 0.01), or TPAW (‐5.9 ± 3.4°C, p = 0.02). Nanoinjection of muscimol in the rRPa prevented IL‐1β‐evoked increases in BAT SNA (p < 0.01), TBAT (p < 0.01), expired CO2 (p < 0.01) and TCORE (p < 0.01), but not in HR (p = 0.08), in comparison to the group that received IL‐1β only. Nanoinjection of muscimol in the rRPa in indomethacin‐pretreated rats prevented IL‐1β‐evoked increases in BAT SNA (p < 0.01), TBAT (p < 0.01), expired CO2 (p < 0.01), TCORE (p < 0.01), and TPAW (p = 0.03), but not in HR (p = 0.12), in comparison to an indomethacin‐pretreated group that received IL‐1β. Nanoinjections of glutamate receptor antagonists in the DMH markedly reduced IL‐1β‐evoked increases in BAT SNA (‐838 ± 542% BL, p = 0.03), TBAT (‐1.1 ± 0.4°C, p = 0.003), expired CO2 (‐0.4 ± 0.1%, p = 0.009) and HR (‐38 ± 20 bpm, p = 0.01), and reduced MAP (‐4 ± ‐2 mmHg, p = 0.02). Plasma PGE2 levels following iv IL‐1β were significantly higher (by ~3 fold) in rats that were not anesthetized when receiving IL‐1b (263.1 ± 136.4 pg/ml) compared to all other groups of rats that were maintained under anesthesia for 2 h (ur/ch anesthetized, saline pretreated: 96.7 ± 30.8 pg/ml, p = 0.007, or indomethacin pretreated: 119.7 ± 51.9 pg/ml, p = 0.02; iso anesthetized, saline pretreated: 82.5 ± 21.2 pg/ml, p = 0.003, or indomethacin‐pretreated: 108.4 ± 39.1 pg/ml, p = 0.01). Therefore, we suggest that the anesthetics used inhibited the systemic production of PGE2. Together, our data suggest that a glutamatergic input to the DMH is necessary for providing the excitatory drive for increasing BAT thermogenesis and tachycardia in response to circulating IL‐1β, likely via rRPa neurons. Additionally, IL‐1β‐evoked CVC requires activation of neurons in the rRPa. These data define critical components of the neural circuit for systemic IL‐1β‐induced fever and provide a foundation for elucidating additional brain mechanisms responsible for COX‐independent fever.