Cathelicidin Antimicrobial Peptide Has Opposite Effects on MS Depending on Which Cells Produce It | Research

The takeaway

In a mouse model of multiple sclerosis, cathelicidin (CRAMP) produced by neutrophils worsened neuroinflammation, while cathelicidin produced by neurons was protective — revealing cell-type-specific roles for this antimicrobial peptide in autoimmune brain disease.

Same peptide, opposite effects
Neutrophil cathelicidin worsens EAE while neuronal cathelicidin protects against it

What the researchers found

Cathelicidin antimicrobial peptide has antagonistic roles in neuroinflammation: neutrophil-derived CRAMP promotes disease in EAE, while neuron-derived CRAMP is protective, demonstrating cell-type-specific immunomodulation.

Why it matters

Multiple sclerosis has no cure, and understanding what drives neuroinflammation is key to finding one. This study reveals that antimicrobial peptides — traditionally thought of as infection fighters — play complex, context-dependent roles in autoimmune brain disease.

The numbers in context

CRAMP produced by CNS-recruited neutrophils at early stage; expressed by neurons with opposing effects on inflammation.

How the study worked

Animal study using EAE (experimental autoimmune encephalomyelitis) mouse model of multiple sclerosis. Investigated cathelicidin (CRAMP) expression in CNS-recruited neutrophils and neurons, and assessed effects on disease progression.

Who was studied

Mice with EAE (experimental autoimmune encephalomyelitis) model of MS

What this study cannot tell us

Mouse model (EAE) — may not fully replicate human MS. CRAMP (mouse) may have different properties than LL-37 (human cathelicidin). Mechanisms underlying the opposite effects not fully characterized. Translation to therapeutic approaches is unclear.

How to read the evidence

Moderate evidence — well-designed animal study with mechanistic insight. EAE is an established MS model but doesn't capture all aspects of human disease.

When this study was published

Published in 2024. Adds to the growing understanding of antimicrobial peptides' immunomodulatory roles beyond infection.

The bigger picture

This finding challenges the simplistic view of antimicrobial peptides as purely defensive molecules. In autoimmune diseases like MS, the same peptide can be both harmful and helpful — suggesting that targeted therapies would need to block neutrophil cathelicidin while preserving neuronal production.

Questions still open

Is LL-37 (human cathelicidin) similarly antagonistic in human MS — harmful from neutrophils, protective from neurons?
Could blocking neutrophil cathelicidin be a therapeutic strategy for MS without affecting neuronal protection?
Do other antimicrobial peptides show similar cell-type-dependent effects in autoimmune diseases?

Common questions

How can the same peptide both cause and prevent brain inflammation?

It depends on which cells make it. When immune cells called neutrophils rush to the brain and release cathelicidin, it ramps up inflammation. But when brain neurons produce the same peptide, it actually calms inflammation down. The cellular context completely changes the peptide's effect.

Could this help treat multiple sclerosis?

Potentially — if we could block cathelicidin from inflammatory immune cells while keeping the brain neurons' protective production intact, it might be a new way to reduce MS-related brain damage. However, this has only been shown in mice so far and needs much more research.

Read the original research

Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation.

The Journal of clinical investigation, 135(3)

View on PubMed ↗Publisher’s paper ↗

Citation

Verma, Subash Chand; Enée, Emmanuelle; Manasse, Kanchanadevi; Rebhi, Feriel; Penc, Axelle; Romeo-Guitart, David; Bui Thi, Cuc; Titeux, Matthias; Oury, Franck; Fillatreau, Simon; Liblau, Roland; Diana, Julien. (2024). Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation.. The Journal of clinical investigation, 135(3). https://doi.org/10.1172/JCI184502