Neurogenic Inflammation

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The neurogenic inflammatory pathway, well described in the skin but also present in deep tissues, involves peripheral nerve endings communicating with skin cells (keratinocytes, melanocytes, fibroblasts, mast cells) and immune cells via neurotrophins and neuropeptides. Mast cells have many neuropeptide receptors secreted by nerves; activation triggers degranulation and release of proteases, cytokines, and histamine. Tryptase binds to PAR-2 receptors, activating them and releasing neuropeptides like CGRP and SP, which drive itching and scratching. PAR-2 activation is linked to pain perception. Tryptase also degrades CGRP, providing negative feedback. SP, through NK-1R and MRGPRX2 on mast cells, activates and degranulates them, intensifying inflammation. This process involves TH2CD4+ immune cells releasing cytokines (IL-4, IL-13, IL-31), which activate receptors on nerve endings and intensify pruritus in skin diseases. Ca2+-dependent TRPV1 and TRPA1 ion channels can interact, and when activated, further increase neuropeptide release, exacerbating neurogenic skin inflammation.

Neurogenic inflammation is a physiological process in which inflammatory mediators are released directly from the peripheral endings of sensory neurons to initiate a rapid, localized inflammatory reaction. This response is clinically characterized by the classic signs of inflammation, including erythema (redness from vasodilation), edema (swelling from plasma leakage), an increase in local temperature, and tenderness or pain.

Comparisons

Comparison with Classical Inflammation

Classical inflammation is the canonical protective and reparative response generated primarily by the immune system when a pathogen or endogenous danger signal is detected. In contrast, neurogenic inflammation is initiated directly by the nervous system. Tissues that are highly exposed to the external environment, such as the skin, lungs, and digestive tract, are densely innervated by nociceptors (sensory nerves that detect noxious stimuli). The transmission of signals through these nerves is almost instantaneous, allowing the nervous system to function as a "first host defense responder," initiating a protective inflammatory cascade faster than the innate immune system can mobilize. Neurogenic and immunogenic inflammation can, and often do, exist concurrently, with each process capable of potentiating the other.

Comparison with Neuroinflammation

Neurogenic inflammation is a fundamentally peripheral phenomenon, wherein sensory nerve endings release mediators that act on surrounding non-neuronal tissues like blood vessels, immune cells, and keratinocytes.

Neuroinflammation, by contrast, is defined as an inflammatory process occurring within the nervous system itself, either in the peripheral nervous system (PNS) or the central nervous system (CNS). The characteristic feature of neuroinflammation is the activation of resident glial cells (such as microglia and astrocytes in the CNS or satellite glial cells in the dorsal root ganglia) which leads to the production of pro-inflammatory cytokines and chemokines within nervous tissue. This process is a primary driver of central sensitisation.

Afferent Nociceptors

The primary neuronal effectors of neurogenic inflammation are the primary afferent nociceptors. These are sensory neurons specialized to detect actual or potential tissue damage. Specifically, the unmyelinated, slow-conducting C-fibers and the thinly myelinated, faster-conducting Aδ fibers are the key neuronal subtypes responsible for initiating the process. These fibers, which are extensively described in the context of nociception, are polymodal, meaning they can be activated by a variety of noxious stimuli, including chemical, thermal, and mechanical insults.

The initiation of neurogenic inflammation begins at the molecular level with the activation of transducer ion channels located on the terminal membranes of these nociceptors. Among the most critical of these are members of the Transient Receptor Potential (TRP) family of ion channels. In particular, TRPV1 (Transient Receptor Potential Vanilloid 1), known as the capsaicin or hot pepper receptor, and TRPA1 (Transient Receptor Potential Ankyrin 1), the "wasabi receptor," are principal detectors of noxious heat and pungent chemical irritants, respectively.

Activation of these channels by a noxious stimulus leads to an influx of cations (primarily Ca2+ and Na+), which depolarizes the nerve terminal. This depolarization, if sufficient to reach threshold, generates an action potential and, critically, triggers the release of pro-inflammatory neuropeptides from the nerve ending into the surrounding tissue. The activation of TRPV1, for example, results in the release of calcitonin gene-related peptide (CGRP) and substance P, which are the principal mediators of neurogenic inflammation.

Antidromic Conduction

Main article: Antidromic Impulses

The primary physiological mechanism that translates a localized noxious stimulus into a widespread inflammatory response is the axon reflex. When a nociceptive nerve ending is activated, the resulting action potential propagates in the normal, or orthodromic, direction along the axon toward the spinal cord, where it transmits nociceptive information to the CNS. However, primary afferent neurons have a branching, tree-like terminal structure in the periphery. At these axonal branch points, the action potential does not only travel centrally; it can also propagate in the reverse, or antidromic, direction down the other collateral branches of the same neuron.

This antidromic impulse travels away from the CNS and back toward the peripheral tissue, invading the full terminal arborization of the neuron. Upon reaching these distal nerve endings, the antidromic action potential triggers the release of neuropeptides into the surrounding microenvironment. This release initiates the cardinal signs of neurogenic inflammation: vasodilation and increased vascular permeability. Because a single neuron can innervate a significant area of tissue, this mechanism allows a point stimulus to produce an inflammatory response over a much wider area than the initial site of injury. This spreading vasodilation is known as the "axon reflex flare" and is a key component of the "triple response of Lewis" (a localized redness at the site of injury, a surrounding flare, and a raised wheal from edema), which is the classic clinical manifestation of neurogenic inflammation in the skin.

Other Models

While the axon reflex is the most well-established mechanism, other models have been proposed to explain the persistence or distant spread of neurogenic inflammation, particularly in chronic pathological states.

Backfiring: This theory suggests that under certain conditions, a sensory neuron may become so irritated or sensitized that an action potential is generated that does not transmit centrally at all. Instead, the impulse may "shoot down the axon directly," causing neuropeptide release at the distal end without any signal ever reaching the spinal cord. It has been proposed that persistent backfiring from a sensitized neuron could be a mechanism underlying sustained, chronic neurogenic inflammation in a specific tissue area.

Neurogenic Switching: A sensory impulse generated at one site is transmitted normally to the CNS. However, instead of simply being processed as a pain signal, the CNS reroutes an efferent-like signal via a different sensory neuron to a distant, secondary location, producing neurogenic inflammation there. This model has been invoked to explain complex phenomena such as multiple chemical sensitivity, where the detection of a chemical irritant by the respiratory system can trigger inflammatory responses in disparate secondary organ systems. These alternative models suggest that the neuronal control of peripheral inflammation may be more complex than the simple axon reflex, involving higher-order processing and pathological neuronal behavior in chronic conditions.

Principal Neuropeptides

Two neuropeptides have long been considered the principal effectors of neurogenic inflammation: Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP). These peptides are synthesized in the neuronal cell bodies located in the dorsal root and trigeminal ganglia and are transported to both the central and peripheral terminals of C- and Aδ-fibers. They are often co-expressed and co-released from the same sensory neurons, yet they perform distinct, complementary roles in the inflammatory response.

Calcitonin Gene-Related Peptide (CGRP): A 37-amino acid peptide and is recognized as the most potent endogenous vasodilator discovered to date. Its primary action is to induce profound and long-lasting relaxation of vascular smooth muscle. This effect is mediated by a specific CGRP receptor, which is a unique hetero-dimeric complex composed of the Calcitonin-Like Receptor (CLR) and a required accessory protein, Receptor Activity-Modifying Protein 1 (RAMP1). These receptors are densely expressed on arterial smooth muscle cells. The release of CGRP from perivascular sensory nerves and its subsequent action on these receptors is the primary driver of the arteriolar vasodilation that produces the characteristic erythema (redness) and flare of neurogenic inflammation. The central role of CGRP in mediating vasodilation, particularly in the trigeminovascular system, has made it a highly successful therapeutic target for the treatment of migraine.

Substance P (SP): An 11-amino acid peptide belonging to the tachykinin family. While CGRP is the master regulator of blood flow, SP's cardinal contribution to neurogenic inflammation is the induction of plasma extravasation. SP acts primarily on post-capillary venules, causing endothelial cells to contract and increasing the permeability of the vessel wall. This allows plasma proteins and fluid to leak from the bloodstream into the surrounding interstitial tissue, resulting in the formation of edema (swelling or a wheal). This effect is mediated predominantly through the activation of the Neurokinin-1 (NK1) receptor. In addition to its vascular effects, SP is a potent modulator of immune cell function, particularly mast cells, with degranulation resulting in amplification of the immune response.

Others: Other members of the tachykinin family such as Neurokinin A (NKA) which also contributes to increased vascular permeability, as well as Vasoactive Intestinal Peptide (VIP), Neuropeptide Y (NPY), and Endothelin-3 (ET-3)

Double knockout mice have been engineered to completely lack the ability to produce both SP and CGRP throughout their nervous system. The results are astonishing: these animals displayed largely intact neurogenic inflammation upon stimulation. Furthermore, they exhibited normal responses to a wide range of acute and chronic pain stimuli, including mechanical, thermal, chemical, and inflammatory pain. Hence while SP and CGRP are sufficient to cause neurogenic inflammation (as injection produces the classic signs), they are not necessary for it. There appears to be a high degree of functional redundancy with other as-yet-unidentified neuropeptides or signalling pathways.

This has profound implications for therapeutic development, suggesting that for complex inflammatory pain conditions, successful therapies may need to target more fundamental upstream mechanisms, such as the activation of the nociceptors themselves, or employ a multi-target strategy rather than focusing on a single neuropeptide.

Mediator	Cellular Source	Primary Receptor(s)	Key Physiological Effects
Substance P (SP)	Sensory Neuron (C/Aδ fiber)	NK1, MRGPRX2	Increased vascular permeability, Mast cell degranulation, Neurotransmitter in pain pathways
CGRP	Sensory Neuron (C/Aδ fiber)	CGRP-R (CLR/RAMP1)	Potent vasodilation (arteriolar), Pain transmission modulation
Neurokinin A (NKA)	Sensory Neuron (C/Aδ fiber)	NK2	Increased vascular permeability, Bronchoconstriction
Histamine	Mast Cell, Basophil	H1, H4	Vasodilation, Increased vascular permeability, Sensory nerve activation (itch, pain)
Tryptase	Mast Cell	Protease-Activated Receptor-2 (PAR-2)	Sensory nerve activation, Pro-inflammatory signaling, Neuropeptide release
Prostaglandins (e.g., PGE₂)	Multiple (incl. Mast Cells, Endothelial Cells)	EP Receptors	Vasodilation, Sensitization of nociceptors (hyperalgesia), Fever
TNF-α	Mast Cell, Macrophage	TNFR1, TNFR2	Pro-inflammatory cytokine signaling, Sensitization of nociceptors

The Neuro-Immune Axis

Main article: The Immune System and Chronic Pain

A purely neuron-centric explanation of neurogenic inflammation, based solely on antidromic impulses and neuropeptide release, is incomplete. What appears to be importance in the transition from an acute, protective response to a chronic, pathological state, is the dynamic, bidirectional communication between the nervous system and the immune system.

At the heart of the neuro-immune axis are mast cells. These are tissue-resident cells of the innate immune system, best known for their role in allergic reactions. They are strategically positioned in tissues at the interface with the external environment, such as the skin, airways, and gastrointestinal tract. They are found in close anatomical proximity to both sensory nerve endings and micro-vessels. This intimate spatial relationship is the structural basis for their function as key transducers and amplifiers of neurogenic signals. Morphological studies using electron microscopy have confirmed direct membrane-to-membrane associations between mast cells and nerves, facilitating rapid and efficient functional communication.

The interaction between sensory nerves and mast cells can a positive feedback loop, which can be understood in two distinct steps.

Step 1: From Nerve to Immune Cell (Nerve-driven Mast Cell Activation)

The process begins when activated sensory nerves release neuropeptides into the tissue. Substance P, in particular, is a powerful activator of mast cells. Upon binding to its receptors on the mast cell surface, SP triggers degranulation, which involves the rapid release of pre-formed inflammatory mediators stored within the cell's cytoplasmic granules.

For many years, it was assumed that SP activated mast cells via its canonical NK1 receptor. However, this did not align with the clinical failure of NK1 antagonists. Research has now identified a novel, mast cell-specific G protein-coupled receptor in humans called Mas-related G protein-coupled receptor X2 (MRGPRX2) (its mouse ortholog is Mrgprb2). Studies have demonstrated that MRGPRX2 is a high-affinity receptor for SP and that SP-mediated mast cell degranulation, inflammatory hyperalgesia, and immune cell recruitment are dependent on this receptor, and surprisingly, are largely independent of the NK1 receptor. This finding provides a compelling molecular explanation for the failure of NK1 antagonists in pain trials; the primary receptor driving SP-mediated neurogenic inflammation in the periphery may not have been the one being targeted.

Step 2: From Immune Cell to Nerve (Mast Cell-driven Nerve Sensitization)

Upon degranulation, mast cells release a potent cocktail of biologically active mediators. This includes pre-formed molecules like histamine, proteases such as tryptase and chymase, and newly synthesized lipid mediators like prostaglandins and leukotrienes, as well as a variety of cytokines (e.g., Tumor Necrosis Factor-alpha (TNF-α)) and growth factors (e.g., Nerve Growth Factor (NGF)).

These mast cell-derived mediators act directly back upon receptors located on the sensory nerve endings.

• First, they can directly activate the neuron, causing it to fire action potentials that are perceived as pain or itch (pruritus). For example, histamine activates H1 and H4 receptors, while tryptase activates Protease-Activated Receptor-2 (PAR-2) on nerve terminals.
• Second, and perhaps more importantly for the development of chronic pain, these mediators sensitize the nerve endings. They lower the activation threshold of the transducer ion channels (like TRPV1), making the neuron hyper-responsive to subsequent stimuli. This state, known as peripheral sensitization, is the neurobiological basis for the clinical signs of hyperalgesia and allodynia.This activation and sensitization of the sensory nerve terminal then leads to the further release of SP and CGRP, which in turn causes further mast cell degranulation, thus completing and powerfully amplifying the positive feedback loop.

Clinical Relevance

Neurogenic inflammation is a central pathophysiological process in a wide spectrum of musculoskeletal and chronic pain disorders. While the initial triggers for these conditions may vary widely (e.g. trauma etc), neurogenic inflammation often serves as a common downstream pathway. It is a "pathophysiological amplifier," driving pain and inflammation. This may explain why seemingly disparate conditions can share some clinical features like allodynia (e.g. an abscess, gout, and CRPS all demonstrate allodynia).

CRPS is widely considered the archetypal clinical manifestation of dysregulated neurogenic inflammation. Pathophysiological show elevated levels of pro-inflammatory cytokines and neuropeptides in the affected tissues and cerebrospinal fluid of CRPS patients. The cardinal signs of CRPS map directly onto the specific mechanisms of neurogenic inflammation":

• Vasomotor: The profound vasomotor changes such as dramatic shifts in skin color (red, mottled, or blue) and temperature are a direct consequence of CGRP-mediated dysregulation of local blood flow.
• Oedema: The persistent oedema and swelling in the affected limb are caused by SP-mediated plasma extravasation and increased vascular permeability.
• Allodynia: The profound allodynia and hyperalgesia are the clinical expression of intense peripheral sensitization, driven by the sustained neuro-immune feedback loop, and subsequent maladaptive neuroplastic changes in the spinal cord and brain (central sensitisation).

Fibromyalgia for many years, it was considered a disorder of purely central pain processing, there is a body of evidence that suggests that peripheral mechanisms, including neurogenic inflammation, play a significant role in initiating and perpetuating the condition.

See Also

• Nociception
• Sensory Physiology
• Antidromic Impulses
• Histamine

Further Reading

Neurogenic inflammation CRPS and fibromyalgia - Littlejohn 2015.pdf- 675 KB (f)

Antidromic vasodilatation and the migraine mechanism - Geppetti 2012.pdf- 233 KB (f)

Antidromic activity neurogenic inflammation - Sorkin 2018.pdf- 1.01 MB (f)

Molecular mechanisms of neurogenic inflammation of the skin - Marek-Jozefowicz 2023.pdf- 3.56 MB (f)