The peripheral nervous system (PNS) participates in local immune regulation through sensory nerves, autonomic nerves, Schwann cells, and satellite glial cells. Immune cells and the cytokines, chemokines, and inflammatory mediators they release can also reciprocally affect neuronal excitability, myelin stability, and axonal regeneration. Neuroimmune interaction is an important mechanistic basis of chronic pain, peripheral nerve injury, autoimmune peripheral neuropathy, and infection-related neuroinflammation.

Keywords: peripheral nervous system; neuroimmune interaction; sensory neurons; Schwann cells; macrophages; T cells; cytokines; neuroinflammation; nerve regeneration; chronic pain

1 Research Entry Points for Peripheral Neuroimmune Interaction

1.1 The Peripheral Nervous System Is Not a Passive Target of Immune Responses

There is continuous information exchange between the peripheral nervous system and the immune system. Sensory nerve endings can sense tissue injury, infection, acidification, mechanical stimulation, and inflammatory mediators, and transmit signals to the central nervous system through action potentials. At the same time, nerve endings can locally release molecules such as substance P (SP), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY), regulating vascular permeability, immune cell recruitment, and inflammatory intensity.

The immune system can also reciprocally affect peripheral nerve function. IL-1β, TNF-α, IL-6, IL-17, GM-CSF, PGE2, and chemokines released by macrophages, T cells, mast cells, and neutrophils can alter neuronal excitability, ion channel expression, and pain sensitization. Peripheral neuroimmune interaction is therefore not a unidirectional process in which “inflammation damages nerves,” but a bidirectional regulatory process among nerves, immunity, and the tissue microenvironment.

1.2 Core Questions in Peripheral Neuroimmune Interaction

Research on peripheral neuroimmune interaction usually focuses on three questions: first, how neural signals regulate local immune responses; second, how immune responses alter peripheral nerve excitability, myelin structure, and axonal integrity; and third, how immune cells and glial cells cooperate in nerve repair after injury. Chronic pain, infectious neuritis, autoimmune peripheral neuropathy, diabetic peripheral neuropathy, and traumatic nerve injury all involve abnormal activation or dysregulated control of these mechanisms.

2 Main Pathways by Which the Peripheral Nervous System Regulates Immune Responses

2.1 Regulation of Immune Cells by the Sympathetic Nervous System

Sympathetic nerve fibers are widely distributed in lymphoid organs, around blood vessels, and in peripheral tissues. Norepinephrine can act on adrenergic receptors on immune cells and regulate the activation states of macrophages, dendritic cells, T cells, and B cells. Different receptor subtypes, local concentrations, and inflammatory stages can lead to different outcomes. In some acute inflammatory settings, sympathetic signaling can limit excessive inflammation; under chronic inflammation or tissue injury conditions, sympathetic signaling may also participate in immune cell recruitment, vascular responses, and pain maintenance.

2.2 The Parasympathetic Nervous System and the Cholinergic Anti-Inflammatory Pathway

Parasympathetic nerves, especially vagus nerve-related cholinergic signaling, can regulate immune cell activation through acetylcholine. Acetylcholine acts on targets such as the α7 nicotinic acetylcholine receptor and can suppress the release of some inflammatory cytokines from macrophages, thereby limiting systemic or local inflammatory responses. Although the vagus nerve is mainly associated with inflammatory regulation in visceral organs, the cholinergic anti-inflammatory pathway provides an important mechanistic framework for peripheral neuroimmune regulation research.

2.3 Sensory Nerve Endings and Neurogenic Inflammation

Nociceptors can directly recognize tissue injury, pathogen-associated molecules, and inflammatory mediators. Activated sensory nerve endings can release neuropeptides such as SP and CGRP, inducing vasodilation, increased vascular permeability, mast cell degranulation, and immune cell recruitment, thereby forming neurogenic inflammation. This process is important in skin inflammation, arthritis, intestinal inflammation, airway inflammation, and neuropathic pain.

3 Effects of the Immune System on Peripheral Nerve Function

3.1 Cytokines Regulate Neuronal Excitability

Inflammatory cytokines can directly or indirectly alter peripheral neuronal excitability. Factors such as IL-1β, TNF-α, and IL-6 can affect sodium channels, calcium channels, TRP channels, and receptor signaling, lowering the threshold of sensory neurons and resulting in hyperalgesia and allodynia. In chronic inflammatory states, persistent release of inflammatory mediators by immune cells can maintain peripheral sensitization for an extended period and further induce central sensitization.

Pain in peripheral neuropathy is not caused only by axonal injury. Inflammatory factors, immune cell infiltration, and nerve-glia interaction are also important mechanisms maintaining chronic pain. The role of cytokines in peripheral neuropathy has been used to explain the potential value of immune cell-targeted therapy for chronic pain.

3.2 Macrophages and Peripheral Nerve Injury

After peripheral nerve injury, macrophages rapidly participate in the clearance of myelin debris, removal of necrotic tissue, and establishment of a repair microenvironment. Early pro-inflammatory macrophages help clear injury residues, but persistent pro-inflammatory responses can aggravate axonal injury and pain sensitization. As repair progresses, macrophages shift toward repair-associated phenotypes and release growth factors and anti-inflammatory mediators, promoting Schwann cell reprogramming and axonal regeneration.

3.3 T Cells, B Cells, and Autoimmune Peripheral Nerve Injury

Autoimmune responses can directly attack peripheral nerve myelin, axons, or ganglionic structures. T cells participate in neuroinflammation through cytokine release and cytotoxic effects. B cells contribute to myelin or axonal injury through antibody production, antigen presentation, and complement activation. Immune synapse formation and immune cell activation mechanisms are important in autoimmune neurological diseases. In the peripheral nervous system, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and some autoantibody-associated neuropathies all reflect the direct effects of the immune system on peripheral nerve structures.

4 Roles of Peripheral Glial Cells in Neuroimmune Interaction

4.1 Schwann Cells Are Important Regulators of Peripheral Neuroimmune Responses

Schwann cells not only form myelin and support axons, but can also transform into a repair-associated state under injury, infection, and inflammatory conditions. After injury, Schwann cells can downregulate myelin-related genes and upregulate chemokines, cytokines, and neurotrophic factors, recruiting macrophages and promoting axonal regeneration. Schwann cells can also participate in antigen presentation and local inflammatory signal amplification, making them an important cell type connecting peripheral nerve structure and immune responses.

4.2 Satellite Glial Cells Regulate Sensory Neuron Excitability

Satellite glial cells in dorsal root ganglia (DRG) and autonomic ganglia surround neuronal somata and can influence neuronal excitability through cytokines, ATP, gap junctions, and ion homeostasis regulation. After inflammation or nerve injury, satellite glial cell activation increases and may promote pain sensitization and the maintenance of neuropathic pain.

4.3 Blood-Nerve Barrier and Immune Cell Entry

Peripheral nerves have a blood-nerve barrier that restricts entry of blood-derived immune cells and inflammatory mediators into the endoneurium. Inflammation, ischemia, infection, or autoimmune responses can disrupt barrier integrity, allowing monocytes, T cells, antibodies, and complement to enter nerve tissue more easily, thereby aggravating neuroinflammation and myelin/axonal injury.

5 Molecular Mechanisms of Neuroimmune Interaction

5.1 Neurotransmitter and Neuropeptide Signaling

Molecules released by peripheral nerves, including norepinephrine, acetylcholine, SP, CGRP, and NPY, can regulate cell migration, phagocytosis, cytokine release, and antigen presentation through receptors on immune cells. The effects of different neurotransmitters on immune responses are not fixed as “pro-inflammatory” or “anti-inflammatory.” Their effects depend on receptor subtype, cell type, inflammatory stage, and the local microenvironment.

5.2 Cytokine and Chemokine Signaling

Molecules released by immune cells, including IL-1β, TNF-α, IL-6, IL-17, IFN-γ, GM-CSF, CCL2, and CXCL1, can act on sensory neurons, Schwann cells, endothelial cells, and immune cells themselves, forming inflammatory amplification loops. The CCL2-CCR2 axis plays an important role in monocyte recruitment and post-injury inflammation after nerve damage. IL-1β, TNF-α, and IL-6 are commonly associated with pain sensitization and maintenance of neuroinflammation.

5.3 Key Intracellular Signaling Pathways

MAPK, NF-κB, JAK-STAT, PI3K-AKT, and NLRP3 inflammasome pathways participate in peripheral neuroimmune interaction. The MAPK pathway can affect neuronal excitability and inflammatory factor expression. NF-κB is an important regulatory node for pro-inflammatory gene transcription. JAK-STAT participates in signal transduction for various cytokines. The NLRP3 inflammasome can promote IL-1β maturation and inflammatory amplification. Abnormal neuroimmune interaction is essentially the result of dysregulation across multiple cells, mediators, and pathways.

6 Immune Responses and Regenerative Repair After Nerve Injury

6.1 Wallerian Degeneration and Immune Clearance

After peripheral nerve injury, distal axons undergo Wallerian degeneration, myelin structures disintegrate, and Schwann cells and macrophages jointly participate in myelin debris clearance. Clearance of myelin debris is a prerequisite for axonal regeneration. If clearance is insufficient, regenerating axonal growth is hindered and the inflammatory state is prolonged.

6.2 Schwann Cell Reprogramming and Formation of Regeneration Bands

After injury, Schwann cells can transform into repair Schwann cells and form bands of Büngner, providing guiding structures for regenerating axons. Repair Schwann cells secrete neurotrophic factors such as NGF, BDNF, and GDNF, and support axonal extension through cell adhesion molecules and matrix remodeling. Inflammatory factors and repair factors produced by immune cells can affect Schwann cell state transitions, thereby determining regeneration efficiency.

6.3 Dual Role of Inflammatory Responses

Moderate inflammation helps clear injured tissue and initiate repair programs. Excessive or persistent inflammation can lead to further nerve fiber injury, pain sensitization, and formation of a scar-like microenvironment. The key to peripheral nerve repair is not complete suppression of immune responses, but control of inflammatory intensity, time window, and cellular phenotype switching.

7 Neuroimmune Abnormalities in Related Diseases

7.1 Neuropathic Pain

Neuropathic pain is usually accompanied by increased sensory neuron excitability, immune cell infiltration, and activation of Schwann cells and satellite glial cells. Mediators such as IL-1β, TNF-α, IL-6, CCL2, and PGE2 can lower neuronal excitability thresholds, causing mild stimuli to evoke pain responses. Chronic pain research needs to focus on both neuronal ion channel changes and remodeling of the immune microenvironment.

7.2 Autoimmune Peripheral Neuropathy

In diseases such as GBS and CIDP, abnormal immune activation can cause myelin or axonal injury. Antibodies, complement, T cells, and macrophages jointly participate in the pathological process, resulting in abnormal nerve conduction, muscle weakness, sensory disturbance, and reduced reflexes. These diseases indicate that peripheral nerve structures can be damaged not only mechanically or metabolically, but can also become targets of immune attack.

7.3 Infection-Related Peripheral Neuroinflammation

Infection can affect peripheral nerves through direct pathogen invasion, immune-mediated injury, or inflammatory mediator release. Cytokines and chemokines induced by local infection can activate nociceptors and cause neuralgia and sensory abnormalities. Some post-infectious immune responses may also induce peripheral nerve demyelination or axonal lesions.

7.4 Metabolic and Degenerative Peripheral Neuropathy

In diabetic peripheral neuropathy, chronic hyperglycemia, oxidative stress, microvascular injury, and low-grade inflammation jointly affect peripheral nerve structure. Macrophage activation, cytokine release, and neurovascular unit injury can aggravate axonal degeneration and pain symptoms. Metabolic peripheral neuropathy should not be understood only as an energy metabolism abnormality, but should also be analyzed within the framework of neuroimmune imbalance.

8 Product Selection Related to Peripheral Neuroinflammatory Cytokines and Signaling Pathways

The core of peripheral neuroimmune interaction lies in bidirectional regulation among neurons, glial cells, and immune cells. Sensory and autonomic nerves can shape local inflammatory responses, while immune factors can also alter neuronal excitability, myelin structure, and the regenerative microenvironment. Combined detection centered on cytokines, chemokines, neuropeptides, glial cell activation, and nerve injury markers helps clarify the mechanisms of peripheral neuroinflammation, pain sensitization, and nerve repair.

References

[1] Kawamura N, Sato K, Fukuda J, et al. The roles of cytokines in peripheral neuropathy: implications for the development of targeted immune cell therapy for chronic pain. Int J Mol Sci. 2020;21(12):4352.

[2] Bramson J, Panosiak M, Feinberg I, et al. Neuro-immune interactions in inflammation and autoimmunity: emerging therapies: part I. Immunology. 2021;164(3):379-396.

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[1] Cholinergic Signaling Modulators