Inflammation is the body’s response to insults. During inflammation, various inflammatory cells are activated to release cytokines and mediators and orchestrate progressing inflammation. Clinically, pneumonia and acute respiratory distress syndrome involve acute inflammation, whereas asthma and chronic obstructive pulmonary diseases represent chronic inflammation. Inflammation is regulated by both the immune and neuroendocrine systems. The central nervous system (CNS) signals the immune system through the autonomic nerves and the hypothalamic–pituitary–adrenal (HPA) axis. Conversely, the immune system signals the brain through mediators and cytokines via the circulation or afferent nerves. Airway sensors activate during lung inflammation to produce responses essential in host defense against infection and trauma. These responses are immediate and non-specific, operating through local or axonal reflexes to amplify the inflammation and enhance immune protection. Simultaneously, signals sent to the CNS promote an anti-inflammatory response to prevent the spread of inflammation and avoid excessive tissue destruction.
The lung has a large surface area that is constantly exposed to environmental pathogens and hazards requiring continuous monitoring and protection by the immune system, to include responses by both its innate and adaptive arms. Innate immunity is non-specific and evokes rapid responses (such as inflammation) to insults. These include first-line filtration and removal systems (such as mucociliary escalator and cough reflex), secreted substances (immunoglobulin A) in mucus and surfactant, which assist in immunity against pathogens, and resident immune cells within the lung parenchyma awaiting any organisms that successfully penetrate the mechanical barriers . Adaptive immunity is specific, in that it first detects the antigen and then mobilizes inflammatory cells targeting that antigen.
The innate and adaptive systems share components and act in concert to defend against pathogens, but, recently, the nervous system was re-discovered as an important player in immune defense as well . The nervous and immune systems interact with one another to maintain homeostasis by sharing ligands and receptors at several levels (Fig. 1).
Figure 1. Schematic illustration of the interaction among the three systems: neural, endocrine, and immune. The double-ended arrows indicate bi-directional interaction. The dotted line with arrows on each end indicates a potential bi-directional interaction. The dotted circle denotes the circumventricular (Circ) organ, a region where the blood brain barrier permits some larger molecules to penetrate. The linking between the circle and three boxes by the solid line indicates a close physical relationship. The immune system is localized in the lung and other visceral organs. It consists of immune cells, which include macrophages, neutrophils, eosinophils, basophils, mast cells, and lymphocytes. These immune cells can release cytokines or mediators, which act locally as paracrine vehicles, or remotely through activation of sensory nerve fibers or through mediators in the circulation.
CNS neurons express pro-inflammatory cytokines, while immune cells express neural mediators and their receptors; thus, neuroimmune interactions form a reflex circuitry to control inflammation. Peripherally derived cytokines may stimulate the neuroendocrine system centrally by crossing the blood brain barrier through circumventricular organs, or in the periphery by stimulating afferent nerves . In turn, the CNS regulates the immune system through neuronal and hormonal pathways, including the sympathetic and parasympathetic nerves, and hormonal responses mainly operating through the HPA axis . Local interaction is generally pro-inflammatory and intensifying; whereas central regulation aims to curtail tissue destruction by restraining inflammation. Over-activation of the immune system leads to inflammatory diseases, whereas under-activation increases susceptibility to infection. This article provides an overview of the complexities of neuroendocrine-immune regulation of inflammation in the lung.
2. Immune response
2.1 Receptors for pathogen recognition
Pathogens are recognized by a set of germ line-encoded receptors known as pattern-recognition receptors (PRRs) . These receptors recognize conserved molecular patterns shared by large groups of microorganisms. Toll-like receptors (TLRs) operate as PRRs in mammals. The TLR family has at least ten members (TLRs 1-10). Among them, TLR4 recognizes lipopolysaccharide (LPS, endotoxin) and the fusion protein of respiratory syncytial virus. In addition, it reacts with endogenous tissue components degraded during the inflammatory response . TLRs may play a role in chronic lung disease.
2.2 Inflammatory cells
Dendritic cells are antigen-presenting cells (APCs) that stimulate naïve T cell proliferation. The dendritic cell recognizes various pathogens. After identifying, ingesting and processing an antigen, it migrates to the lymph nodes and presents the antigen to resident T cells, thus inducing the immune response. Macrophages reside in the lung and are the main source of cytokines, chemokines, and other inflammatory mediators that propagate or suppress the immune response . Neutrophils are the first cells to be recruited to sites of infection or injury, and target microorganisms and tumor cells . After phagocytosis, neutrophils kill ingested microbes with reactive oxygen species, antimicrobial proteins, and degradative enzymes. Lymphocytes consist of T cells (cellular immunity) and B cells (humoral immunity). T lymphocytes include CD8+ (cytotoxic) and CD4+ (helper) cells, with the latter further classified into Th1 and Th2. A balanced Th1 and Th2 response is needed in face of an immune challenge , while a dysregulated response may lead to chronic inflammatory conditions like asthma and chronic bronchitis . Th1 cells produce interferon (IFN)-gamma and TNF-alpha to drive cellular immunity to eliminate intracellular parasites, viruses and cancer cells. Th2 cells produce IL-4, -5, -9, and -13 to drive humoral immunity to fight extracellular organisms. Mast cells are activated by various stimuli to produce histamine, leukotrienes, proteases, cytokines, chemokines and other substances that cause acute as well as chronic airway inflammation . Eosinophils are often associated with parasite infections, allergic diseases, and chronic lung inflammatory states. They produce major basic proteins, lipid mediators, cytokines and growth factors . Although the inflammatory cells take center stage, epithelial, endothelial and mesenchymal cells also participate in the inflammatory process .
Cytokines are small signaling molecules produced by cells, serving as autocrine, paracrine or endocrine mediators to regulate immunity and inflammation. Cytokines bind to membrane receptors and activate second messengers to alter cell protein expression, proliferation and secretion. Different cells may secrete the same cytokine; a given cytokine may act on different types of cells. Different cytokines may produce similar functions. Cytokines may act as chemokines to attract inflammatory cells .
Cytokines can be categorized as pro-inflammatory (TNF-alpha, IL-1beta, IL-6, IL-8, and IFN-gamma) or anti-inflammatory (IL-10, TGF-beta, and IL-1ra). Pro-inflammatory cytokines activate the immune system and participate in the acute inflammatory response. Among them, TNF-alpha and IL-1beta are most important. They stimulate antigen presentation, adhesion molecule expression on endothelial cells, inflammatory cell activity as well as expression of matrix degrading enzymes. In the lung, alveolar macrophages secrete the anti-inflammatory cytokines to suppress the inflammatory response . IL-10 inhibits the production of pro-inflammatory cytokines by T cells, NK cells and monocytes . Receptors for TGF-beta are present on virtually all cells. TGF promotes wound healing and scar formation. Increasing evidence shows that many lung diseases are associated with dysregulation of cytokines. For example, in allergic asthma, APCs activate Th2 cells to produce IL-4 and IL-13, which cause B cells to produce IgE and subsequent mast cell degranulation. In the meantime, Th2 cells also stimulate IL-5 production to activate eosinophils . Activation of mast cells and eosinophils may lead to an asthmatic attack. Chronic obstructive pulmonary disease is associated with TNF-alpha, IFN-gamma, IL-1β, IL-6 and GM-CSF . In acute respiratory distress syndrome, TNF-alpha and IL-1beta are increased significantly  while IL-10 is relatively lower . The imbalance of pro- and anti-inflammatory cytokines serves to promote these diseases.
2.4 Regulation of lung inflammation
Inflammatory responses are important mechanisms for host defense and must be tightly regulated. An insufficient response provides too little protection, while an over-reaction induces tissue destruction, so protective mechanisms exist in the lung. For example, activation of TLRs may suppress Th1- and Th2- mediated inflammation, thus providing negative feedback to prevent excessive lung inflammation . In addition, cytokines produced by inflammatory cells such as IL-10  and TGF-beta  can down regulate inflammatory cytokine production and inflammatory response. The lungs also provide organ-specific regulatory strategies to prevent excessive inflammation during microbial invasion, such as Type II epithelial cells in the lung which communicate with alveolar macrophages, providing tonic inhibitory effects through TGF-beta to limit potential adaptive immune-induced lung inflammation .
Recently, it has been recognized that inflammation in a variety of organs including the lung is regulated through neural immune interaction . The interaction involves the peripheral and central nervous systems. Sensory neurons in the lung may detect the inflammatory intensity and send the signals to the brain. Indeed, pulmonary sensory neurons are activated during acute lung injury , and activated by pro-inflammatory cytokines and mediators, and TLR ligands . This activation may initiate a reflex to suppress production of pro-inflammatory cytokines  to contain inflammation. On the other hand, activation of sensory afferents may release neuropeptides, inducing neurogenic inflammation to intensify the inflammatory response.
3. Sensory nerves in inflammatory amplification
Stimulation of pulmonary sensory nerves not only activates local cellular networks through axonal and local reflexes to amplify the response, but also signals the brain to regulate the response.
3.1 Afferent nerves
Airway sensor neurons (or sensors) convert mechanical or chemical information in the lung into electrical signals transmitted to the CNS through vagal and sympathetic afferents. At least five types of airway sensors run in the vagus nerves. The rapidly adapting receptors, slowly adapting receptors, and deflation-activated receptors are mechanosensors, whereas high-threshold Adelta receptors and C-fibers receptors are chemosensors (nociceptors or nocisensors) . In addition, the lung contains aggregated neuroendocrine cells called neuroepithelial bodies (NEBs), which are richly innervated and also believed to be sensors . Reflexes initiated from airway sensors can be categorized as regulatory or protective (defensive) . The mechanosensors serve mainly regulatory functions to control breathing pattern and airway tone. Chemosensors are stimulated by a variety of chemical agents, and trigger powerful defense reflexes to expel or deter the entry of irritants into lower airways. Interestingly, intravenous injection of LPS stimulates airway nocisensors within 1 minute , and local injection of LPS into the sensory fields activates the sensors within a few seconds (personal observation), suggesting that LPS may directly activate vagal afferents through TLR4 and trigger innate immune responses. Indeed, TLR4 mRNA and protein are expressed in the sensory neurons and the nodose ganglion in rats . Since activation of nocisensors causes neurogenic inflammation (see below), these sensors are part of the innate immune system for host defense, providing a fast immune response.
Morphological studies demonstrate the presence of sympathetic afferents within the lungs ; their activity has been electrophysiologically recorded in stellate ganglia  and white rami of T2-T4 . Stimulation of pulmonary sympathetic afferent alters breathing pattern. In vagotomized rabbits, activation of pulmonary sympathetic afferents by directly injecting bradykinin into the lung parenchyma produces profound cardiopulmonary reflex effects, including stimulated inspiration and expiration, bradycardia, and hypotension . Furthermore, bradykinin elicits both respiratory excitation and inhibition, indicating multiple pathways in the sympathetic afferent system. As evidenced by electrical recording, some T3 spinal sensory neurons respond to ammonia inhalation. The response can be abolished by resiniferatoxin, which debilitates nocisensors . Taken together, the sympathetic sensors in the lung are a heterogeneous group and are polymodal nocisensors that participate in pathological processes.
3.2 Ligands activating nociceptive sensors
During lung inflammation, a variety of neural, epithelial, endothelial, and phagocytic cells produce inflammatory mediators that activate airway nocisensors. These include: IL-1beta, TNF-alpha, tachykinins , such as substance P (SP), calcitonin gene related peptide (CGRP), prostaglandins, bradykinin, adenosine, 5-hydroxytryptamine (5-HT), histamine, and reactive oxygen species (ROS) [24,36]. Their effects involve airway smooth muscle contraction, mucus secretion, increased vascular permeability, and inflammatory cell activation. During airway mucosal inflammation, tachykinin content in nociceptive afferents increases . SP and, to a lesser extent, CGRP cause airway vasodilatation and protein extravasation into the mucosa by increasing vascular permeability. Arachidonic acid is liberated from membrane-bound phospholipids by phospholipase A2, forming inflammatory mediators [prostaglandins E and F, prostacyclin (PGI2), and thromboxanes, and leukotrienes] that activate nocisensors . These mediators stimulate or sensitize the nocisensor in response to chemical or mechanical stimuli . Mast cells are the major source for 5-HT, histamine, arachidonic acid metabolites, tryptase , and nerve growth factor , while neutrophils effectively generate ROS, which are nocisensor activators (Fig. 2).
Figure 2. Schematic depiction of airway nociceptor inter-reacting with different structures in the lung. Airway nociceptors send their afferent (solid line) to the cell body in the nodose and jugular ganglia, and then further ascend to the NTS, where the information is integrated. The vagal motor neurons in the nucleus ambiguus as well as the dorsal motor nucleus of the vagus send their efferent (doted line) to parabronchiole ganglia. Here synapses are made and the neurons send post-ganglionic fibers to many effectors (gland, arterioles and venuoles).
A variety of chemical substances, including free radicals, mediators, and cytokines, are produced in the lung from different sources, such as epithelial cells [including the neuroepithelial body (NEB)], mast cells, macrophages, neutrophils, and eosinophils. These chemicals stimulate the airway sensors, in addition to inter-reacting with other cell populations, to initiate reflexes and produce local effects. Under the influence of these chemical substances, the sensor’s response is reshaped (plasticity). Please note that stimulation of nociceptors, for example by exposure to stimulants after epithelial damage, can cause an axon reflex to affect effectors, or cause a classical reflex action, by transmitting the information to the NTS. In addition, the stimulation can possibly cause local reflexes to influence the effectors by feeding the information into the parabronchiole ganglion. Mast cells contain 5-HT, histamine, arachidonic acid metabolic products, tryptase, and nerve growth factor. NEBs contain 5-HT, substance P (SP), calcitonin gene related peptide (CGRP), and adenosine triphosphate (ATP). Abbreviations: para. gang., parabronchiole ganglion; s.m., smooth muscle; epith., epithelium; a., arteriole; v., venuole; M, macrophage; E, eosinophil; N, neutrophil; AA, arachidonic acid; NGF, nerve growth factor; NKA, neurokinine A; NTS, nucleus tractus solitarius; ECP, eosinophilic cationic protein; MBP, major basic protein; ROS, reactive oxygen species.
During inflammation, pro-inflammatory and anti-inflammatory cytokines are mobilized. Simultaneous increase in pro- and anti-inflammatory mediators is beneficial, because it provides dual, bidirectional mechanisms for better control.
3.3 Neurogenic inflammation
Neurogenic mechanisms play a key role in airway inflammation . Electrical stimulation of vagal efferents produces neurogenic inflammation by releasing neuropeptides from nociceptive endings . Neurogenic inflammation is a non-specific mechanism, which may serve as an amplifier for inflammatory processes. During pathogen invasion, allergic reaction, or traumatic injury, the nocisensor is activated and the inflammatory process is enhanced. Sensory activation releases neuropeptides like SP that cause airway epithelial cells, mast cells, and macrophages to release inflammatory mediators including TNF . Activation of neurokinin receptors up regulates inflammatory cytokine expression . Inflammatory cytokines such as IL-1beta may induce airway hyper-responsiveness by enhancing SP expression in airway nerves ; nocisensors and resident cells that release mediators and chemokines are further stimulated. Chemokines attract phagocytes, such as macrophages and neutrophils, to engulf pathogens and destroy the invading organisms. Thus, sensory activation forms a positive feedback loop to amplify the initial stimulatory effects and promote innate host defense. Furthermore, SP stimulates T cells to produce interferon-gamma  to exert cellular immunity and also act as chemoattractant for dendritic cells and recruit them into inflammatory sites . Dendritic cells are professional antigen presenting cells that stimulate naïve T cell proliferation. Thus, by releasing neuropeptides, airway sensors may also facilitate adaptive immune response. Indeed, morphological studies show close contact between airway sensory nerves and dendritic cells .
3.4 Cell-cell networks accelerating inflammatory process
Mediators from multiple cellular sources (epithelium, endothelium, smooth muscle, and immune cells) activate nocisensors by multifaceted actions. Some mechanisms are as follows. 1) A given receptor, such as the TRPV-1 receptor, may have many structurally different activators. 2) A particular pathway can be altered by numerous endogenous agents. For example, COX-2, which is one of the main sources for production of inflammatory mediators during pulmonary diseases , can be induced by pro-inflammatory cytokines and growth factors, but inhibited by steroids. 3) An agent may act through multiple pathways in a given cell, or in different types of cells. For example, ROS activate TRPV-1 and P2X purinoceptors in nociceptors . The released nerve growth factor (NGF) from mast cells up regulates TRPV-1 expression on a sensor, and induces COX-2 in adjacent epithelial cells. Both enhance the inflammatory response. 4) A particular agent may stimulate the nocisensor by multiple cellular actions via different mechanisms. For example, bradykinin can activate the nocisensor directly, but also indirectly by increasing the production and release of prostenoids (PGI2 and PGE2 from the epithelium), cytokines (IL-1 and TNF-alpha from immune cells), and neuropeptides (SP, Neurokinin A, CGRP by axon reflex). Furthermore, SP induces histamine release from mast cells. Together, SP, CGRP, PGE2 bradykinin, and histamine increase capillary permeability to facilitate access to nocisensors by blood-borne mediators. Increased local temperature and decreased pH due to inflammation also contribute to sensory activation.
A constellation of mediators is released during inflammation. Each not only produces inflammation, but also stimulates airway sensors either directly or indirectly. Redundancy produces additive or synergistic effects and ensures sensor activation. Sensory activation may cause local and axon reflexes, which sets up a positive feedback system to amplify inflammation by increasing the concentration and types of mediators. In addition, each of the agents may trigger production and release of other pro-inflammatory mediators by paracrine effects, which produce secondary effects on a cell population. Secondary effects can trigger tertiary effects and so forth. Neurogenic inflammation and cell-cell interaction in the network are essential for inflammatory amplification. However, the positive feedback system has to be buried by a negative feedback system to prevent self-destruction.
4.0 Neuroendocrine control of immune system
4.1 Hypothalamus as an integrating center
The hypothalamus is not only an important integration center for body temperature, food intake, the autonomic nervous system, circadian rhythm, and sexual behavior, but also in immune responses and stress . The anterior and posterior aspects of the hypothalamus were once thought to be parasympathetic and sympathetic centers, respectively. Electrical stimulation of the anterior caused bradycardia and hypotension. Stimulating the posterior produced defense reactions, including hypertension, rapid breathing, pupil dilation and piloerection . The paraventricular nucleus (PVN) of the hypothalamus is important in neural, endocrine and immune interaction.
The vagus nerves serve as the hard wire connecting the lung to the brain. Airway afferents first terminate at the nucleus tractus solitarius (NTS) , which is the major relay station for visceral sensory inputs and also receives nociceptive information from somatic afferents . Injecting neural tracer into the nodose ganglia lights up the NTS . Intravenous or intraperitoneal injection of LPS or IL-1beta induces Fos expression in the nodose ganglia  and the NTS . In turn, the NTS projects to diverse regions related to sickness response and to PVN neurons, which are responsible for the synthesis and release of corticotropin-releasing hormone (CRH). Multiple, convergent inputs from NTS neurons project polysynaptically to the PVN . Injection of IL-1beta into the lateral ventricle induces Fos expression in neurons that produce CRH in the PVN . Intravenous injection of IL-1beta increases Fos expression in the hypothalamus, which can be blocked by interruption of the ascending fibers from NTS to PVN neurons . Electrical stimulation of the vagal afferents increases expression of mRNA and protein levels of IL-1beta as well as CRH mRNA in the hypothalamus. Additionally, it increases plasma levels of adrenocorticotropin (ACTH) and corticosterone. This indicates HPA activation .
4.2 Neuroendocrine and sympathetic system
The hypothalamic-pituitary-target organ axes, especially the HPA, forms a circuit with the peripheral nervous system in immunoregulation. Neuropeptides in the HPA are powerful immunoregulators that exert their effects on lymphoid cells and CNS neurons, in addition to stimulating glucocorticoid production . The immune system signals inflammation to the neuroendocrine system through cytokines. Interleukin-1beta and TNF-alpha are major mediators during an acute inflammation ; they induce profound neuroendocrine and metabolic changes by signaling the CNS. Upon stimulation, the PVN secretes CRH to the hypophysis. CRH then stimulates the anterior pituitary gland to release ACTH, which in turn causes release of glucocorticoids from the adrenal glands. Glucocorticoids regulate gene expression and function in immune cells, suppressing the expression of cytokines, adhesion molecules, chemoattractants, and inflammatory mediators. They also influence immune cell trafficking, migration, maturation, and differentiation . Glucocorticoids shift the immune response from cellular immunity (Th1) to humoral immunity (Th2), and from a pro-inflammatory profile to an anti-inflammatory profile .
Sympathetic nerves innervate immune organs such as the thymus, spleen, and lymph nodes . Lymphocytes express adrenergic receptors (AR) and therefore can respond to neurotransmitters released from sympathetic nerves. Activation of the HPA axis regulates fever and other stress responses, leading to glucocorticoid production, sympathetic stimulation and catecholamine release. Catecholamines inhibit pro-inflammatory cytokine production of TNF-alpha and interferon-gamma, and stimulate anti-inflammatory cytokine production of IL-10 and transforming growth factor-beta , thus exerting varied effects. For example, they increase pro-inflammatory cytokine production by activating alpha2-AR, but inhibit it by activating beta2-AR . In turn, intravenous administration of IL-1beta increases sympathetic outflow in splanchnic and renal nerves. Intraperitoneal injection of IL-1beta increases norepinephrine turnover in the lung, spleen, and pancreas .
4.3 Vagal-vagal control system
Recently, a cholinergic anti-inflammatory reflex has been proposed as initiated by stimulation of vagal afferents; it exerts anti-inflammatory effects through acetylcholine (ACh) released from vagal efferents . ACh can act on N (nicotinic) and M (muscarinic) receptors. Anti-inflammatory action occurs through stimulation of N receptors expressed on the surface of the macrophage. It reduces nuclear effector (NF-kB) activation and TNF-alpha production. Electrical stimulation of vagal efferents during endotoxemia inhibits TNF-alpha synthesis in the liver and prevents endotoxemic shock . Furthermore, using nicotine to activate cholinergic anti-inflammatory pathways reduces mortality associated with endotoxemia . In humans, nicotine exposure attenuates the febrile response to intravenous injection of LPS and promotes the anti-inflammatory profile (increased blood IL-10 and cortisol levels) . Conversely, the CNS may exert a pro-inflammatory effect to control the immune system by releasing ACh, which acts at M3 receptors on alveolar macrophages and increases chemotactic activity in neutrophils, monocytes and eosinophils . Injection of IL-1beta into sensory fields stimulates airway nocisensors , supporting their role in host defense.
The large surface area of the lungs not only favors gas exchange, but also pathogen contact. An ideal defense provides a forceful immune response (such as inflammation) to eliminate pathogens, with no extensive inflammation to disable the vital function of the lung. Airway sensors monitor immunologic and inflammatory information by detecting mediators released from multiple cells in the lung. Sensory activation forms positive feedback acting locally to amplify the signals. This leads to clearance of pathogens, airway remodeling, or perpetuation of diseases. Sensory activation also signals the CNS to initiate a systemic anti-inflammatory response through the HPA axis and autonomic nervous system to contain the inflammation. Such an intensified focal inflammation with an extensive anti-inflammatory response is an important mechanism for lung homeostasis.
5-hydroxytryptamine (5-HT); acetylcholine (ACh); adrenergic receptor (AR); adrenocorticotropin (ACTH); antigen presenting cells (APCs); calcitonin gene related peptide (CGRP); central nervous system (CNS); corticotropin-releasing hormone (CRH); granulocyte-macrophage colony-stimulating factor (GM-CSF); T helper cell (Th); hypothalamic-pituitary-adrenal (HPA) axis; immunoglobulin (Ig); interferon (IFN); interleukin (IL); lipopolysaccharide (LPS); muscarinic (M); nerve growth factor (NGF); neuroepithelial bodies (NEBs); nicotinic (N); nucleus tractus solitarius (NTS); paraventricular nucleus (PVN); pattern-recognition receptors (PRRs); prostacyclin (PGI2); reactive oxygen species (ROS); substance P (SP); Toll-like receptors (TLRs); transforming growth factor (TGF); transient receptor potential vanilloid receptors (TRPV-1); tumor necrosis factor (TNF)
Department of Pulmonary Medicine, and Department of Physiology and Biophysics, University of Louisville, Louisville, KY, USA 40292; and Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China 200032
Corresponding Author: Jerry Yu, Email: firstname.lastname@example.org
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