By Katharine Sedivy-Haley, PhD Candidate, Hancock Lab, CBR

Inflammation is an important component of our body’s defence system, but excessive or inappropriate inflammation is the main cause behind many human diseases, including Alzheimer’s, atherosclerosis, and rheumatoid arthritis. Immunosuppressive therapies are often used to treat such disorders, but these treatments also increase the patient’s risk of infection. In a recent paper¹, Bing Catherine Wu and Amy Lee of the Hancock Lab identify a new potential therapy without this downside: Innate Defence Regulator (IDR) peptides.

IDR peptides are synthetic versions of Host Defence Peptides, naturally occurring molecules which modulate the immune system in addition to having direct antimicrobial activity (as previously covered by the CBR). Wu and Lee investigated IDR peptide 1002, which has been previously demonstrated to dampen inflammation during bacterial infection while preserving or enhancing the body’s ability to fight infection. However, it had not yet been determined whether IDR-1002 would have similar activity in instances of sterile inflammation not caused by bacteria, such as in arthritis or atherosclerosis. Using a mouse ear model, Wu and Lee discovered that the peptide does indeed have strong anti-inflammatory effects in sterile, chemically induced inflammation.

The researchers first determined that in vitro, IDR-1002 dampened the production of inflammatory mediators: IL-6, MCP-1, CXCL1 and reactive nitrogen species in cultured monocytes/macrophages. To study this effect in vivo, the researchers topically applied the inflammatory agent PMA to mouse ears, immediately followed by IDR-1002 or the nonsteroidal anti-inflammatory drug indomethacin. The application of PMA alone causes the recruitment of inflammatory mediator cells such as neutrophils, and leads to visible swelling or edema, within 6 hours of treatment. Peptide treatment significantly suppressed both the influx of neutrophils and the observed swelling. The peptide also reduced the local levels of IL-6, MCP-1, CXCL1, and reactive oxygen and nitrogen species. These effects were comparable to those of indomethacin, suggesting potential therapeutic application.

To understand the function of IDR-1002 in more depth, the researchers then used RNA-Seq to compare the genetic expression within ear tissue after treatment with a solvent control, PMA, and both PMA and the peptide. PMA treatment was confirmed to increase the expression of genes associated with inflammation, including cytokine signalling, especially IFN-γ, TNF-α, and IL-1 cascade, and class A/1 rhodopsin-like receptors including chemokine receptors. However the PMA/peptide combination downregulated many of these pathways, including genes responsible for recruiting inflammatory cells such as neutrophils, and the IFNγ pathway which is known to be essential in PMA-induced inflammation. Peptide treatment suppressed a subset of rhodopsin-like receptor genes recognizing pro-inflammatory mediators such as prostaglandin and histamine. The rhodopsin-like receptors are a major family of the G-coupled protein receptor (GPCR) group. Interestingly, under conditions of bacterial infection IDR-1002 can act on one or more unidentified GPCR receptors to increase chemokine production and neutrophil infiltration², which suggests that these peptides may have different effects depending on the inflammatory trigger. In the sterile context, the anti-inflammatory effect of IDR-1002 is likely contributed by the suppression of an IFN regulatory factor 8–regulated network, which is known to control central inflammatory pathways.

While IDR-1002 shows compelling anti-inflammatory properties, additional experiments are necessary to confirm the safety and effectiveness of IDR-1002 in humans. Wu currently plans to test the peptide in a more human-like context, for example in an ex-vivo human skin model. Hopefully, IDR-1002 or similar peptides can be developed into therapeutics capable of reducing inflammation in a variety of non-infectious diseases without weakening the patient’s immune response system.

1. Wu, B. C., Lee, A. H.-Y. & Hancock, R. E. W. Mechanisms of the Innate Defense Regulator Peptide-1002 Anti-Inflammatory Activity in a Sterile Inflammation Mouse Model. J. Immunol. 199, 3592–3603 (2017).
2. Nijnik, A. et al. Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment. J. Immunol. 184, 2539–2550 (2010).