Modulation of outer membrane vesicle-based immune responses by cathelicidins.
Balhuizen. Melanie D MD; Versluis. Chantal M CM; van Grondelle. Monica O MO; Veldhuizen. Edwin J A EJA; Haagsman. Henk P HP
Key Findings
- LL‑37, CATH‑2, PMAP‑36 and K9CATH altered macrophage cytokine responses to B. bronchiseptica outer membrane vesicles
- The modulation differed between spontaneous and heat‑induced vesicles, suggesting preparation‑dependent effects
- TLR4 was the dominant signaling route, and cathelicidins likely act by binding LPS rather than blocking vesicle uptake
Practical Outcomes
- The findings suggest LL‑37 might help dampen harmful inflammation from bacterial components, but no human dosing or delivery guidance is provided. For biohackers, it’s an interesting mechanistic clue rather than a ready‑to‑use protocol, so further research is needed before practical application.
Summary
Scientists showed that the human peptide LL‑37 and similar cathelicidins can change how immune cells react to tiny bubbles (outer membrane vesicles) released by a Gram‑negative bacterium, mainly by calming the strong inflammation caused by LPS. The effect varies depending on how the vesicles are prepared, indicating LL‑37 could be used to fine‑tune immune responses, but the work is still early and done only in cell cultures.
Abstract
Antibiotic resistance is increasing and one strategy to prevent resistance development is the use of bacterial vaccines. For Gram-negative bacteria, natural outer membrane vesicles (OMVs) could be used for vaccine development. These vesicular structures are naturally produced by all Gram-negative bacteria and contain several antigens in their native environment. However, despite that the presence of lipopolysaccharide (LPS) may aid as intrinsic adjuvant, there is a risk that it may also cause undesired immune responses. Therefore, molecules to dampen LPS-induced toll-like receptor (TLR) 4 activation may be needed. Here host defense peptides (HDPs), like cathelicidins, can play an important role. They have been shown to interact with LPS and thereby neutralize LPS-induced TLR4 activation. However, there is currently no knowledge about neutralization in an OMV-based setting. Therefore, in this paper the immune modulating capacity of HDPs was investigated after macrophage stimulation with either spontaneous or heat-induced B. bronchiseptica OMVs. This revealed that the cathelicidins LL-37, CATH-2, PMAP-36 and K9CATH were able to modulate immune responses. Interestingly, immune modulation by these cathelicidins was different for spontaneous compared to heat-induced OMVs. Interaction studies revealed that the mode of binding of cathelicidins to OMVs slightly differed between OMV classes. Furthermore, TLR screening revealed that TLR2, 4, 5 and 9 were involved in stimulation of macrophages by OMVs, with TLR4-mediated activation being the most important pathway. Uptake of OMVs did not play a major role in macrophage activation. Taken together, this study shows how OMVs can activate macrophages and how cathelicidins may modulate these immune responses.
Study Information
pubmed
2022
2022-03-17T00:00:00.000Z
10.1016/j.vaccine.2022.03.015
9
52