Acute hypoxia activates the neuroimmune system, which diabetes exacerbates

Abstract

Acute hypoxia is experienced in an array of ailments and conditions, including asthma, chronic obstructive pulmonary disease, heart failure, sleep apnea, acute hypotension, and blast lung injury. Classically, infection activates the neuroimmune system, causing loss of interest in the social environment. We report that the non-infectious stimulus acute hypoxia triggers neuroimmune system activation (NSA), causing loss of interest in the social environment, and that recovery from hypoxia-induced NSA is impaired in a mouse model of type 2 diabetes. Importantly, recovery from the behavioral consequences of hypoxia-induced NSA was nearly ablated in MyD88 (myeloid differentiation factor 88) knock-out mice and in mice intracerebroventricularly administered the caspase-1 inhibitor ac-YVAD-CMK (ac-Tyr-Val-Asp-2,6-dimethylbenzoyloxymethylketone). Diabetic mice had prolonged recovery from NSA that could be halved by administration of subcutaneous interleukin-1 (IL-1) receptor antagonist (RA). These results show that acute hypoxia activates the IL-1beta arm of the neuroimmune system, which diabetes exacerbates and treatment with IL-1RA ameliorates.

Figure 1.

Acute hypoxia activates the neuroimmune system. A, C57BL/6J mice were exposed to 8% oxygen and 92% nitrogen (hypoxia) or atmospheric air (normoxia) for 2 h. SE was measured immediately before hypoxia (−2 h), after hypoxia (0 h), and at 2, 6, 10, and 22 h after restoration to atmospheric conditions. Results are expressed as percentages of the baseline measurement, means ± SEM; n = 6; *p < 0.05, hypoxia versus normoxia. B, Mice (C57BL/6J, db/db, and db/+) were treated as in A, and SmVO₂ was measured at the times indicated, means ± SEM; n = 5; *p < 0.05, control versus hypoxia versus after hypoxia. C, Mice were treated as in A, and real-time RT-PCR was used to quantify IL-1β, IL-1RA, and IL-1R2 from whole brain at the times indicated. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 5; *p < 0.05 hypoxia versus normoxia. D, Mice were treated as in A, and hippocampus was examined at 22 h after hypoxia. H&E stain, 40×. Results are representative; n = 3.

Figure 2.

IL-1β mediates recovery from hypoxia-induced NSA. A, MyD88 KO mice or MyD88^+/+ mice were exposed to hypoxia or normoxia for 2 h. SE was measured immediately before hypoxia (−2 h), after hypoxia (0 h), and at 2, 6, 10, and 22 h after restoration to atmospheric conditions. Results are expressed as percentages of the baseline measurement, means ± SEM; n = 5; *p < 0.05 hypoxia versus normoxia; ^†p < 0.01 MyD88^−/− hypoxia versus C57BL/6J hypoxia. B, C57BL/6J mice were intracerebroventricularly administered ac-YVAD-CMK or vehicle control 30 min before exposure to hypoxic or normoxic conditions for 2 h. SE was measured and reported as in A; n = 5, *p < 0.05 hypoxia versus normoxia. C, Mice (db/+) were injected subcutaneously with Kineret (IL-1RA) (1.4 mg/kg) or vehicle control 1 h before a 2 h exposure to hypoxia or normoxia. SE was measured immediately before hypoxia (−2 h), after hypoxia (0 h), and at 2, 6, 10, and 22 h after restoration to atmospheric conditions. Results are expressed as percentages of the baseline measurement, means ± SEM; n = 6; *p < 0.05 hypoxia versus normoxia.

Figure 3.

db/db mice have impaired recovery from hypoxia that can be corrected with Kineret. A, Mice (db/db and db/+) were exposed to hypoxia or normoxia for 2 h. SE was measured immediately before hypoxia (−2 h), after hypoxia (0 h), and at 2, 6, 10, and 22 h after restoration to atmospheric conditions. Results are expressed as percentages of the baseline measurement, means ± SEM; n = 5; *p < 0.05 hypoxia versus normoxia. B, Mice (db/db) were treated as in A, and real-time RT-PCR was used to quantify IL-1β, IL-1RA, and IL-1R2 from whole brain at the times indicated. Results are expressed as relative change in mRNA expression (ΔmRNA), means ± SEM; n = 5; *p < 0.05 hypoxia versus normoxia. C, Mice (db/db) were injected subcutaneously with Kineret (IL-1RA) (1.4 mg/kg) or vehicle control 1 h before a 2 h exposure to hypoxia or normoxia. SE was measured and reported as in A; n = 6. *p < 0.05 hypoxia versus normoxia.