Neuropeptide substance P worsens bone infection by boosting chemokine release from infected bone cells | Research

The takeaway

Substance P augments chemokine release from S. aureus-infected osteoclasts via NK-1 receptors, promoting leukocyte recruitment and bone destruction, with NK-1R inhibition ameliorating disease severity in a mouse osteomyelitis model.

NK-1R blockade reduces osteomyelitis
Inhibiting substance P's receptor reduced bone infection severity by decreasing inflammatory cell recruitment and bone destruction in mice

What the researchers found

Substance P increases chemokine release (not gene expression) from S. aureus-infected osteoclasts but not osteoblasts. NK-1R inhibition reduced disease severity in mouse osteomyelitis. Reduced leukocyte-attracting chemokines and osteoclast/neutrophil activity in vivo.

Why it matters

Staphylococcal osteomyelitis is difficult to treat and causes progressive bone destruction. Identifying substance P as a driver of this destruction—and showing NK-1R blockade helps—opens a new therapeutic avenue for a challenging infection.

How the study worked

In vivo mouse staphylococcal osteomyelitis model with NK-1R inhibition. In vitro bone marrow-derived osteoclast cultures with S. aureus infection ± substance P. Gene expression and protein release assays.

What this study cannot tell us

Mouse model may not fully represent human osteomyelitis. Only substance P tested—other neuropeptides may be involved. NK-1R antagonists are available (aprepitant) but not tested for osteomyelitis clinically.

How to read the evidence

Well-designed preclinical study with both in vivo disease model and in vitro mechanism. Strong proof of concept.

When this study was published

Published in 2025.

The bigger picture

This study highlights the neuro-immune-bone axis in infection—how nerve-derived peptides influence immune responses in bone. Targeting neuropeptide signaling could complement antibiotic therapy for bone infections.

Questions still open

Could NK-1R antagonists (like aprepitant) be repurposed for bone infections?
Do other neuropeptides contribute to osteomyelitis severity?
Is substance P a biomarker for bone infection severity?

Common questions

How does a nerve peptide make bone infections worse?

Substance P, released by nerve fibers in bone tissue, acts on osteoclasts (bone-destroying cells) during bacterial infection, causing them to release more inflammatory signals (chemokines) that recruit immune cells. While this immune response is meant to fight infection, it actually causes excessive bone destruction.

Could blocking substance P help treat bone infections?

Yes, in this mouse study, blocking substance P's receptor (NK-1R) reduced infection severity and bone destruction. NK-1R blockers like aprepitant are already used for nausea prevention and could potentially be repurposed for bone infections, though human studies are needed.

Read the original research

Substance P Augments Chemokine Production by Staphylococcus aureus Infected Murine Osteoclasts.

Inflammation, 48(5), 3506-3518

View on PubMed ↗Publisher’s paper ↗

Citation

Sipprell, Sophie E; Krueger, Quinton A; Mills, Erin L; Marriott, Ian; Johnson, M Brittany. (2025). Substance P Augments Chemokine Production by Staphylococcus aureus Infected Murine Osteoclasts.. Inflammation, 48(5), 3506-3518. https://doi.org/10.1007/s10753-025-02280-x