The role of neutrophils in neuro-immune modulation

Abstract

Neutrophils are peripheral immune cells that represent the first recruited innate immune defense against infections and tissue injury. However, these cells can also induce overzealous responses and cause tissue damage. Although the role of neutrophils activating the immune system is well established, only recently their critical implications in neuro-immune interactions are becoming more relevant. Here, we review several aspects of neutrophils in the bidirectional regulation between the nervous and immune systems. First, the role of neutrophils as a diffuse source of acetylcholine and catecholamines is controversial as well as the effects of these neurotransmitters in neutrophil's functions. Second, neutrophils contribute for the activation and sensitization of sensory neurons, and thereby, in events of nociception and pain. In addition, nociceptor activation promotes an axon reflex triggering a local release of neural mediators and provoking neutrophil activation. Third, the recruitment of neutrophils in inflammatory responses in the nervous system suggests these immune cells as innovative targets in the treatment of central infectious, neurological and neurodegenerative disorders. Multidisciplinary studies involving immunologists and neuroscientists are required to define the role of the neurons-neutrophils communication in the pathophysiology of infectious, inflammatory, and neurological disorders.

Keywords: Adrenoceptors; Neuroimmunology; Neuroimmunomodulation; Neuroinflammation; Neutrophil; Nicotinic receptors.

Fig. 1.. The neuro-immune interactions of neutrophils.

(A) Neutrophils contribute to the neuronal regulation of the immune system. Neurotransmitters produced by either neuronal pathways (such as norepinephrine produced by the splenic nerve) or immune cells (acetylcholine produced by T lymphocytes) modulate neutrophil activity and the production of secondary messengers that, in turn, regulate both neurons and immune cells (including neutrophils by autocrine mechanism). (B) Neutrophils also modulate neuronal sensory signals by producing neurotransmitters to regulate the activation, sensitization, and maintenance of sensory neurons as observed in pain. Sensory neurons can also modulate neutrophils inhibiting their microbicidal functions by releasing neuropeptides. (C) Neutrophils can also cross the blood-brain-barrier (BBB) and release cytotoxic and inflammatory factors that induce neuronal damage in the central nervous system and contribute to neurological and neurodegenerative disorders.

Fig. 2.. Bidirectional regulation of sensory neuron-neutrophil functions.

Infection or tissue damage induces the production of inflammatory factors such as arachidonic acid metabolites and prostanoids that (A) increase tissue permeability to circulating neutrophils, and (B) can induce nociception and pain by activating sensory neuronal pathways. (C) The activation of nociceptive terminals triggers an axonal reflex that generates neurogenic substance P (SP) and calcitonin gene-related peptide (CGRP) increasing tissue permeability and inhibiting neutrophil microbicidal functions (neurogenic inflammation). (D) Neutrophils migrate into tissue to produce cytokines and chemokines that attract other leukocytes such as mast cells and circulating neutrophils. (E) Infiltrated neutrophils are activated and can produce multiple factors such as prostaglandin E₂ (PGE₂), sympathetic amines, reactive oxygen species (ROS), hydrogen protons (H⁺), and metalloproteases that modulate nociceptors and inflammatory pain.

Fig. 3.. Role of neutrophils in the central nervous system.

A) During the presence of neurodegenerative (e.g. Alzheimer), inflammatory (e.g. stroke) or infectious (e.g. sepsis, viral infection) conditions in the central nervous system (CNS). (B) Resident cells, such as astrocytes and NK cells, release different chemotactic substances, mainly chemokines. (C) These chemical mediators allow neutrophils to cross the blood-brain barrier (BBB) and produce high quantities of harmful mediators to neurons, such as reactive oxygen and nitrogen species (ROS and RNS), neutrophil extracellular traps (NETs) and cytokines. (D) In addition, these mediators induce microglial activation, ruptures on BBB, and demyelination and axonal loss. (E) The pharmacological activation of nicotinic receptors by acetylcholine or nicotinic agonists decreases neutrophil infiltration to the CNS by reducing the levels of chemokines.