Related Experiment Video

Updated: Jun 4, 2026

Teasing Out the Interplay Between Natural Killer Cells and Nociceptor Neurons
09:40

Teasing Out the Interplay Between Natural Killer Cells and Nociceptor Neurons

Published on: June 30, 2022

Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release

Han Meng1, Wenchao Hu1, Enming Kang1

  • 1Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, the Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China; The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi'an 710032 Shaanxi, P.R. China.

Cell Reports
|June 2, 2026
PubMed

Insights

MLKL

Area of Science:

  • Neuroscience
  • Immunology
  • Pain Research

Background:

  • Neuroinflammation in the dorsal root ganglion (DRG) has complex roles in chronic pain.
  • The precise mechanisms of DRG neuron-neutrophil interactions in pain are not fully understood.

Purpose of the Study:

  • To investigate the role of MLKL in DRG neuron-neutrophil interactions and chronic pain.
  • To elucidate the molecular cascade linking MLKL, histone H3, and neutrophil extracellular traps (NETs) in pain.

Main Methods:

  • Examined MLKL localization and histone H3 binding in nociceptive neurons.
  • Investigated the effects of peripheral inflammation on MLKL/H3 interaction and histone H3 release.
  • Assessed the impact of extracellular histone H3 on neuronal activity, NET formation, and hyperalgesia.
  • Utilized nociceptive-specific MLKL depletion and genetic MLKL knockout (Mlkl-/-) mouse models.
  • Tested therapeutic interventions including extracellular histone neutralization and DNA clearance.

Main Results:

  • MLKL is constitutively nuclear in nociceptive neurons, binding to histone H3.
  • Inflammation disrupts MLKL/H3 interaction, causing MLKL translocation and histone H3 release.
  • Extracellular histone H3 promotes neuronal hyperactivity, NET formation, and hyperalgesia via P2X7R and TLR4.
  • Nociceptive MLKL depletion reduces pain threshold and enhances NET formation independently of cell death.
  • Targeting extracellular histone, DNA, or MLKL nuclear localization ameliorates hyperalgesia and NETosis.

Conclusions:

  • A novel MLKL-histone H3-NET cascade in nociceptive neurons mediates DRG neuron-neutrophil interactions.
  • This pathway contributes significantly to chronic inflammatory pain.
  • The MLKL-histone-NET axis represents a potential therapeutic target for managing chronic pain.
Keywords:
CP: neuroscienceMLKLhistoneinflammatory painneutrophil extracellular trap

More Related Videos

Real-Time, High-Throughput Microscopic Quantification of Human Neutrophil Extracellular Trap Release and Assessing the Pharmacology of Antagonists11:32

Real-Time, High-Throughput Microscopic Quantification of Human Neutrophil Extracellular Trap Release and Assessing the Pharmacology of Antagonists

Published on: October 18, 2024

Morphological and Compositional Analysis of Neutrophil Extracellular Traps Induced by Microbial and Chemical Stimuli14:05

Morphological and Compositional Analysis of Neutrophil Extracellular Traps Induced by Microbial and Chemical Stimuli

Published on: November 4, 2022

Related Concept Videos

Cells of the Innate Immune Response01:28

Cells of the Innate Immune Response

The innate immune response is an immediate and non-specific response against pathogens, acting swiftly to prevent the spread of infections. The primary cells involved in this response are phagocytes and natural killer (NK) cells.
Phagocytes
Phagocytes police the peripheral tissues by removing cellular debris and responding to the invasion of foreign substances or pathogens. Many phagocytes attack and remove microorganisms even before lymphocytes detect them. The human body has two general...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Nociception01:44

Nociception

Nociception—the ability to feel pain—is essential for an organism’s survival and overall well-being. Noxious stimuli such as piercing pain from a sharp object, heat from an open flame, or contact with corrosive chemicals are first detected by sensory receptors, called nociceptors, located on nerve endings. Nociceptors express ion channels that convert noxious stimuli into electrical signals. When these signals reach the brain via sensory neurons, they are perceived as pain. Thus, pain helps the...
Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
Neuromuscular Junction And Blockade01:29

Neuromuscular Junction And Blockade

The site of chemical communication between a motor neuron and a muscle fiber is called the neuromuscular junction (NMJ). The end of the motor neuron at the NMJ divides into a cluster of synaptic end bulbs. The cytoplasm of these bulbs consists of synaptic vesicles enclosing acetylcholine molecules, the principal neurotransmitter released at the NMJ. The region opposite the synaptic bulb that ends in the muscle fiber is called the motor end plate, which has acetylcholine receptors. Within the...
Immune Surveillance by NK Cells and Phagocytes01:25

Immune Surveillance by NK Cells and Phagocytes

Immune surveillance is an integral part of the innate immune system, involving the continuous monitoring of peripheral tissues to detect and respond to pathogens, infected cells, or cancerous cells. This surveillance is conducted primarily by natural killer (NK) cells and phagocytes, which employ distinct but complementary mechanisms to identify and eliminate threats.
Natural Killer Cells: The Fast Responders
NK cells are large granular lymphocytes found in the blood and lymphatic system. These...