Volume 6, Issue 1 , Pages 23-26, January 2012
Neural regulation of the immune system modulates hypertension-induced target-organ damage
Article Outline
Abstract
Innate and acquired immune mechanisms are involved in hypertension-induced target-organ damage. Immunosuppressive treatments directed at T lymphocytes, NF-κB activation, or tumor necrosis factor-alpha production are all successful in ameliorating cardiac or renal injury. Recently, important modulatory functions involving the autonomic nervous system have been uncovered. Involved are an afferent detection arm that sends vagal-mediated signals to the brain and an efferent arm that includes the spleen and important nicotinic acetylcholine receptor subunit. The signaling attenuates inflammatory activity. Splenectomy or operations that injure the vagus or splenic abrogate these important protective mechanisms. Vagal stimulation, either electrical or pharmacological, could provide additional protection. The field of neuroimmunology will become increasingly important to cardiovascular clinicians.
Keywords: Neuroimmunology, target-organ damage, hypertension, immune mechanisms, angiotensin
Introduction
A highlight of this year’s American Heart Association Council for High Blood Pressure Research (2011) annual meeting was a symposium of the same name as this article’s title. That target-organ damage in hypertensive models and patients involves immune cells has been known for decades.1 We and others have shown that by treating angiotensin (Ang) II-induced hypertensive models with dexamethasone, myocphenolate mofetil, or entanercept, target-organ damage in the heart and the kidney is markedly ameliorated.2, 3 The immunosuppressive approaches are all fairly nonspecific. As a result, nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) is less activated. Lymphocyte production is reduced. Subsequently, tumor necrosis factor-alpha (TNF-α) production is diminished. All three responses are intimately involved in innate and acquired immunity. The Harrison laboratory made the seminal observation that lymphocyte-deficient recombination activating gene (Rag1) knockout mice exhibit very little blood pressure elevation when Ang II is infused.4 Reconstituting B lymphocytes does not alter this phenotype. However, restoring T cells normalizes the expected effects of Ang II. The result is not a sole function of Ang II administration, because a second animal model, desoxycorticosterone-salt, yielded the same results. Our group made similar observations in DNA-binding protein inhibitor-2 (ID-2) knockout mice that have several defects including failure to produce dendritic cells.5
The Harrison laboratory next made the striking observation that anteroventral third cerebral ventricle (AV3V) lesions in mice prevented the expected actions of infused Ang II. The group found that the elevation in blood pressure in response to Ang II was virtually eliminated by AV3V lesions, as was activation of circulating T cells and the vascular infiltration of leukocytes.6 To determine whether or not T-cell activation and vascular inflammation were related to central influences or were mediated by blood pressure elevation, the authors administered hydralazine in the drinking water. The group found that hydralazine prevented the hypertension and abrogated the increase in circulating activated T cells and vascular infiltration of leukocytes caused by Ang II. The Harrison laboratory concluded that the central and presser effects of Ang II are critical for T-cell activation and development of vascular inflammation. The findings also support a “feed-forward” mechanism in which modest degrees of blood pressure elevation lead to T-cell activation. This activation in turn promotes inflammation and further raises blood pressure, leading to severe hypertension.
This remarkable paper would have surely interested Michael Brody, who developed the AV3V lesion (which destroys several brain nuclei).7 The lesion also abrogates two-kidney-one-clip Goldblatt hypertension, presumably by interfering with sympathetic activation in this model.7 First, direct central actions of Ang II, acting through receptors in the subfornical organ and organum vasculosum of the lamina terminalis, increase sympathetic discharge and secretion of vasopressin through mechanisms integrated at the level of the AV3V region. Second, sensory systems originating in the kidney activate increased sympathetic discharge through complex projection pathways involving forebrain systems. Mineralocorticoid hypertension appears to involve enhanced secretion of vasopressin and central vasopressinergic mechanisms also dependent on the AV3V region. Third, reciprocal connections between key central areas involved in control of arterial pressure provide the neuroanatomical basis for central nervous system participation in hypertension. These were seminal observations indeed, and it is exciting that the findings have now been rediscovered.
Additional exciting information comes from the Paton laboratory. Paton and his group pointed out that a neurogenic component to primary hypertension is well established.8 Along with raised vasomotor tone and increased cardiac output, chronic activation of the sympathetic nervous system in hypertension has a diverse range of pathophysiological consequences independent of any increase in blood pressure. Paton et al provided a perspective on the actions and interactions of Ang II, inflammation, and vascular dysfunction/brain hypoperfusion in the pathogenesis and progression of neurogenic hypertension. The work involved exciting direct supravital imaging into brain tissues, including the use of fluorescent fusion proteins. The group’s most recent work targeted the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. The investigators were able to draw connections between ischemic brain responses and inflammatory reactions. It would appear that local brain ischemia could mediate inflammation, even systemically.
Also illuminating was the work of the Tracey laboratory.9 Their work pointed out inflammation can cause damage and death, even without known bacterial or viral cause; we call it all “sepsis.” The Tracey laboratory asked a pivotal question: “What controls this primitive and potentially lethal innate immune response to injury and infection?” Molecular and neurophysiological studies during the past decade have revealed astounding answers, and the Tracey laboratory provided most of these responses. They found that neural circuits coordinate immunity. Furthermore, the circuits operate reflexively. The afferent arc of the reflex consists of nerves that sense injury and infection. Their signals activate efferent neural circuits within the brain, including the cholinergic anti-inflammatory pathway that modulates immune responses and the progression of inflammatory diseases. The group showed that the efferent arc is the cholinergic anti-inflammatory pathway. This pathway inhibits innate immune responses in the spleen (innervated by a single parasympathetic nerve) through inhibitory signals that arise within the brain stem, traverse the vagus nerve, and signal through nicotinic acetylcholine receptor subunit α7 (α7nAChR). Cytokine-producing immune cells uniquely express this receptor. The entire process leads to the suppression of NF-κB activation and the inhibition of innate immune responses. Those of you from my generation will remember that vagotomy-and-pyloroplasty was the usual operation for gastrointestinal hemorrhage. Patients undergoing splenectomy are at risk for Pneumococcal sepsis. The Bilroth operation (type II) is a risk for reactivation of tuberculosis. “Older” audience members can only ask, “what have we done?”
Be aware that the initiation of the inflammatory reflex by many possible ligands through key receptors is a crucial point of innate immune control. Thus, information from many stimulating molecules is processed by a smaller number of pattern-recognition receptors that transduce signaling information to a small number of transcription factors. NF-κB is again in the foreground because the mechanism regulates innate immune responses. Maximal control is thereby derived from a circuit in which the inflammatory reflex targets this restricted point of information processing. Double-stranded RNA, high-mobility-group-protein B1 (HMGB1), IκB, inhibitor of NF-κB, and interleukin-1α (IL-1α) are intimately involved in this process. Activated macrophages and monocytes secrete HMGB1 as a cytokine mediator of inflammation. Antibodies that neutralize HMGB1 confer protection against damage and tissue injury during arthritis, colitis, ischemia, sepsis, endotoxemia, and systemic lupus erythematosis. The mechanism of inflammation and damage is binding to Toll-like receptor-4 (TLR4), which mediates HMGB1-dependent activation of macrophage cytokine release. This state of affairs positions HMGB1 at the intersection of sterile and infectious inflammatory responses. These findings are summarized in a figure adapted from a review by the authors (Figure 1). Very recently, the Tracey laboratory identified an acetylcholine-producing, memory phenotype T-cell population in mice that is integral to the inflammatory reflex.10 The acetylcholine-producing T cells were required for the inhibition of cytokine production by vagus nerve stimulation. Thus, action potentials originating in the vagus nerve regulate T cells, which in turn produce the neurotransmitter acetylcholine required to control innate immune responses. The functional role for acetylcholine-producing memory T cells, as an integral component of a neural information system controlling immunity, is surprising. My interpretation is that T cells are innervated.
Figure 1
Shown is the neural circuitry of the inflammatory reflex.9 The inflammatory reflex controls innate immune responses by a mechanism that targets the regulatory transcription factor nuclear factor-κB (NF-κB). Exogenous and endogenous molecular products of infection and injury interact with receptors that are expressed by cells of the innate immune system, including Toll-like receptors (TLRs) and nucleotide-binding domain (NLRs). Ligand–receptor interactions activate innate immune responses and induce the secretion of pro-inflammatory cytokines. These molecules also activate afferent sensory neurons, which constitute the sensory arc of the inflammatory reflex. Axons travelling in the vagus nerve relay this information as action potentials to the brain stem. This interconnection in turn activates the efferent arc, which is known as the cholinergic anti-inflammatory pathway. Subsequent signaling inhibits innate immune responses in the spleen through inhibitory signals that arise in the brain stem, traverse the vagus nerve and signal through nicotinic acetylcholine receptor subunit α7 (α7nAChR), which is expressed by cytokine-producing immune cells. This leads to the suppression of NF-κB activation and the inhibition of innate immune responses. The inflammatory reflex could be initiated by many possible ligands through key receptors of the innate immune control. A multifactorial process is clearly involved.
Adapted from Tracey et al.9
Although we have only recently appreciated these mechanisms, they have accompanied our evolution for billions of years. When the primitive nematode worm, Caenorhabditis elegans, gets infected, the pathogen stimulates the worm’s innate immune response and activates the synthesis of new proteins.11 The reaction probably causes the accumulation of unfolded proteins in the worm’s cells. This state of affairs activates the “unfolded protein response.” The worm has sensory neurons, termed ASH and ASI. These neurons regulate the innate immune response to infection by blocking the unfolded protein response in nonneuronal cells. The surface receptor in the worm is called OCTR-1, which is a putative catecholamine receptor in sensory neurons. Thus, from worms to humans, an evolutionary scheme has been established allowing the immune system to detect changes in the environment. The detection modifies the behavior of the host. The loop is closed by reflex signals that originate in the nervous system. These signals adjust immune responses and thereby maintain homeostasis.
The Abboud laboratory put autonomic regulation of the cardiovascular system on the map more than 50 years ago and produced a host of novel findings. The group is investigating dysregulation of innate immunity in genetic hypertension. Their model involves harvested splenocytes from the spleens of spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY). The splenocytes from both groups were characterized in terms of TNF-α, IL-6, and IL-10 production after activation of the Toll-like receptors on the cells. The effects of Ang II, norepinephrine, and nicotine (to activate the α7nAChR) were also examined. The data are not yet published. But the lymphocyte response patterns in WKY and SHR were markedly different: WKY cells reacted appropriately, whereas SHR cells exhibited inflammatory responses. The data suggest that “dysautonomia” in SHR and subsequent dysregulation of the immune system are a part of the pathogenesis of genetic hypertension.
Finally, what are the therapeutic ramifications of this discussion? Can vagal tone be increased to augment dampening the immune system? Fascinating studies have appeared. For instance, Zhang et al randomized 15 dogs to control and vagal nerve stimulator (pace maker–like device) groups.12 All dogs underwent 8 weeks of high-rate ventricular pacing for the first 4 weeks to develop heart failure and another 4 to maintain heart failure. They then delivered concomitant vagal nerve stimulation or sham together with the ventricular pacing. At 4 and 8 weeks of ventricular pacing, both left ventricular end-diastolic and end-systolic volumes were lower and left ventricular ejection fraction was higher in the stimulated group than in the control group. Heart rate variability and baroreflex sensitivity improved in the stimulated dogs. Plasma norepinephrine, Ang II, and C-reactive protein levels, ordinarily expected to be elevated in this model, were markedly attenuated with vagal nerve stimulation. Isolated reports of vagal stimulation for cardiovascular disease in humans exist in the literature. Vagal stimulation may evolve as a useful therapeutic adjunct. Possibly, pharmacological treatments could be helpful here. We showed earlier that in mice, alpha-2 adrenoceptor activation with clonidine exerted a regulatory influence on autonomic cardiovascular control and baroreflex function.13 The effect of clonidine on baroreflex heart regulation was mediated by the parasympathetic nervous system. Our murine data fit well with recent human observations regarding parasympathetic activation via alpha-2 adrenoceptors. Clonidine has side effects and is disliked by most patients. However, additional studies in this regard could be useful.
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PII: S1933-1711(11)00242-7
doi:10.1016/j.jash.2011.09.006
© 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.
Volume 6, Issue 1 , Pages 23-26, January 2012
