CCL2-CCR2 Driven Macrophage Infiltration Selectively Strips Fast-Fatigable NMJs…

Mechanistic description

CCR2+ monocyte-derived macrophages, recruited to the neuromuscular junction by motor neuron-secreted CCL2, selectively infiltrate and strip fast-fatigable (IIb/IIx fibre) NMJs via matrix metalloproteinase-9 (MMP-9) cleavage of the laminin alpha-5/beta-2 NMJ scaffold. Fast motor neurons express higher CCL2 and lower TIMP-1 (MMP-9 inhibitor) than slow motor units, creating a chemokine gradient that explains selective NMJ vulnerability. Genetic or pharmacological MMP-9 blockade should preferentially protect fast-fatigable NMJs in ALS mouse models.

Mechanism / pathway

CCL2
→
CCL2-CCR2 / MMP-9 / NMJ remodelling
→
ALS

Evidence for (5)

MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology.

PMID:31666087 2019 J Neuroinflammation
The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis.

PMID:40750607 2025 Nat Commun
Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients.

PMID:21569455 2011 J Neuroinflammation
CCR2 is localized in microglia and neurons, as well as infiltrating monocytes, in the lumbar spinal cord of ALS mice.

PMID:32349774 2020 Mol Brain
Possible association between expression of chemokine receptor-2 (CCR2) and amyotrophic lateral sclerosis (ALS) patients of North India.

PMID:22685564 2012 PLoS One

Evidence against (2)

Evidence matrix

5 supporting 0 contradicting

100% supporting

Supporting

MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology. PMID:31666087 · 2019 · J Neuroinflammation
The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis. PMID:40750607 · 2025 · Nat Commun
Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients. PMID:21569455 · 2011 · J Neuroinflammation
CCR2 is localized in microglia and neurons, as well as infiltrating monocytes, in the lumbar spinal cord of ALS mice. PMID:32349774 · 2020 · Mol Brain
Possible association between expression of chemokine receptor-2 (CCR2) and amyotrophic lateral sclerosis (ALS) patients of North India. PMID:22685564 · 2012 · PLoS One

Contradicting

No contradicting evidence recorded.

Cite this hypothesis

Citation

etl-backfill (2026). CCL2-CCR2 Driven Macrophage Infiltration Selectively Strips Fast-Fatigable NMJs…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/44b404ab-eabb-45a2-ab3a-9e2f3ecf3b7b

BibTeX

@misc{scidex_hypothesis_44b404ab,
  title        = {CCL2-CCR2 Driven Macrophage Infiltration Selectively Strips Fast-Fatigable NMJs…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/44b404ab-eabb-45a2-ab3a-9e2f3ecf3b7b},
  note         = {SciDEX artifact hypothesis:44b404ab-eabb-45a2-ab3a-9e2f3ecf3b7b}
}