Neuroimmune modulation of cardiorespiratory responses to acute severe hypoxia

Hypoxia poses a significant stress to physiological function, with some notable exceptions. Acute reflex cardiorespiratory responses serve to restrain overt tissue hypoxia by maximizing oxygen uptake and delivery, thereby limiting the magnitude of oxygen deficiency and otherwise potentially deleterious effects on tissue performance. These powerful, highly co-ordinated reflexes are complemented over longer time domains by the transcriptional regulation of cellular defence strategies. Temporal plasticity within complex physiological networks provides a capacity for acclimatization to hypoxia, allowing lowlanders to breathe the rarefied air atop the roof of the world. Adaptation over thousands of years has crafted the unique physiology of the Sherpa people. It is now also recognized that aberrant plasticity in respiratory–autonomic coupling presents in response to patterns of intermittent hypoxia characteristic of human sleep-disordered breathing. There is a growing appreciation of hypoxia-dependent inflammatory signalling in many fields of study. Indeed, neuroimmune interactions are a topical centrepiece of contemporary biomedical scientific enquiry. Surprisingly, there remains a relative paucity of knowledge in respect of hypoxia-dependent immunomodulation of cardiorespiratory control, although one senses that this is about to change. In this issue of Experimental Physiology, Silva et al. (2018) explore the hypothesis that cardiorespiratory responses to hypoxia are shaped by neuroimmune interactions in the CNS. Male rats pretreated for 5 days with minocycline, an inhibitor of microglial activation, or vehicle-treated control animals, were surgically instrumented for arterial blood pressure recordings and 1 day later exposed to normoxia or sustained hypoxia (fractional inspired O2 = 0.08) for 3 h. After gas exposures, cardiovascular recordings were performed in conscious rats over the course of the hypoxic exposure during periods of quiet basal activity. Thereafter, the density of activated neurons andmRNA levels of acute inflammatory cytokines were determined in brainstem and hypothalamic nuclei crucial in the orchestration of autonomic and neuroendocrine responses to stress. Exposure to acute hypoxia of merely 3 h (albeit severe) increased the expression of inflammatory genes in key brain regions. Interleukin (IL)-6, IL-1β and tumour necrosis factor-α mRNA were significantly elevated in the rostral ventrolateral medulla (RVLM), containing the C1 catecholaminergic neurons pivotal to the elaboration of cardiovascular responses to hypoxia (Guyenet et al., 2013). These changes were accompanied by increases in IL-6 and IL-1βmRNA in the paraventricular nucleus of the hypothalamus (PVH), which receives ascending projections from RVLM C1 neurons and is recognized as a key integrative site in autonomic and endocrine control, crucial to neuroimmune interplay in the brain. Minocycline treatment decreased IL-1β mRNA and tumour necrosis factor-α in RVLM but not PVH and, interestingly, increased IL-6 mRNA levels in both RVLM and PVN, suggesting that microglia ordinarily regulate IL-6 levels in these brain regions. Pretreatment with minocycline significantly decreased the number of hypoxia-activated RVLM C1 (−52%) and PVH (−42%) neurons, with no change in the density of hypoxia-activatedneurons of the caudal nucleus tractus solitarii, revealing no apparent change in peripheral chemosensory input to the brainstem. An apparent specificity of the effect ofmicroglial inactivationwas evident, becauseminocycline treatment did not affect the numberof activatedneurons innormoxic animals, nordid it affect thedensityof hypoxia-activatednon-C1 (tyrosinehydroxylase-negative) neurons of theRVLMor the number of hypoxia-activated neurons of the supraoptic nucleus of the hypothalamus. Thus,microglia appear to influenceRVLM C1–PVH neuronal activation selectively in response to hypoxia, purportedly increasing network activity crucial to autonomic control in response to hypoxic stress, albeit inferred from a study of their presumed inactivation byminocycline. To determine the integrative physiological response to minocycline treatment, Silva et al. (2018) assessed blood pressure and autonomic balance in rats in response to severe hypoxia by spectral analysis of pressure recordings. In addition, ventilation was determined by whole-body plethysmography. Surprisingly, in the light of the findings described above, there was no difference in mean arterial pressure between vehicleand minocycline-treated animals throughout the time course of the 3 h hypoxic exposure. A modest sympathovagal imbalance producing tachycardia was noted after 1 h of hypoxia. Arguably the most striking observation of the study by Silva et al. (2018) was a finding of blunted ventilation during hypoxia in minocyclinetreated rats compared with vehicle-treated control animals, whereas normoxic ventilation was unaffected by minocycline treatment. The suppression of hypoxic ventilation is consistent with recent observations thatmicroglial inactivation blunts time-dependent ventilatory responses to hypoxia (Lorea-Hernández, Morales, Rivera-Angulo, Alcantara-Gonzalez, & Peña-Ortega, 2016; Stokes, Arbogast, Moya, Fu, & Powell, 2017; Tadmouri, Champagnat, &Morin-Surun, 2014). The observation of Silva et al. (2018) suggests a dynamic contributory role formicroglia and neuroimmune interactions as an essential component of the integrative ventilatory response to acute severe hypoxia, which clearly warrants further investigation to delineate the underlying mechanism, with prostaglandin E2 a probable candidate. The finding adds to a growing interest in the