["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend This study investigated arterial–internal jugular venous (IJV) exchange of cytokines in response to low‐intensity and maximal cycling exercise at sea level and following 6–8 days at 3800 m a.s.l. There was a shift towards net release of interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), monocyte chemoattractant protein‐1 (MCP‐1) and macrophage inflammatory protein‐1 beta (MIP‐1b) following maximal exercise at both altitudes, driven by an increase in internal jugular venous concentration. The results of this study indicate that partial acclimatization at 3800 m a.s.l. does not alter the physiological release of cytokines from the brain in response to maximal exercise.\n\n\n\n\n\n\n\n\n\nAbstract\nHow neuroinflammation is altered at high altitude (HA) is equivocal, and it is unclear whether and how exercise alters this inflammatory response. We tested the hypothesis that maximal exercise at HA exacerbates the neuroinflammatory response. Healthy adults (n = 12, 6/6 females/males) completed 60 min of steady‐state semi‐recumbent low‐intensity cycling exercise and an incremental maximal test at sea level (SL) and following 6–8 days at 3800 m a.s.l. (HA). Radial arterial and internal jugular venous (IJV) sampling and duplex volumetric blood flow of the internal carotid and vertebral arteries was used to assess trans‐cerebral exchange of cytokines at rest and 5 min after maximal exercise (POST‐MAX‐5). Arterial–IJV uptake/release of cytokines at rest was not different between altitudes. Arterial leucocytes were increased by 57%–66% at POST‐MAX‐5 at both SL (P < 0.001) and HA (P < 0.001); exercise × altitude, P = 0.433, with no difference between arterial and IJV. Apart from a trivial absolute increase in arterial interleukin‐6 at HA (Δ +0.62 pg ml−1, 95% confidence interval [0.10, 1.15], P = 0.022), the remaining 16 of the 17 measured systemic cytokines were unaffected by maximal exercise at both altitudes (P > 0.05). There was a shift towards trans‐cerebral net release by −1.3 to −8.2 pg ml−1 (P < 0.05) of interleukin‐6, interleukin‐8, monocyte chemoattractant protein‐1 and macrophage inflammatory protein‐1 beta at POST‐MAX‐5 at both altitudes. The release of these cytokines occurred independently of systemic inflammation and altitude exposure. The results of this study indicate that partial acclimatization at 3800 m a.s.l. does not alter the physiological release of cytokines from the brain in response to maximal exercise.\n\n\n\n\n\n\n\n\n\nKey points\n\nSystemic inflammation is altered at high altitude, but it is unclear how exercise at altitude affects inflammation in the brain.\nWe tested the hypothesis that maximal exercise will augment the cerebrovascular inflammatory response at high altitude.\nExposure to 6–8 days at high altitude did not evoke systemic or brain inflammation at rest and did not exacerbate responses to maximal exercise.\nThere was a shift towards net release of interleukin‐6, interleukin‐8, monocyte chemoattractant protein‐1 and macrophage inflammatory protein‐1 beta following maximal exercise at both altitudes, driven by an increase in internal jugular venous concentration.\nThese new results show that the adaptive physiological response to exercise involves net release of select cytokines from the brain; this occurred in the absence of systemic inflammation and irrespective of high altitude.\n\n\n"]