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Heteroaggregation of Antimicrobial Peptides LL-37 and HNP‑1 Drives Cooperative Neutralization of Cytotoxicity

Jing Zhang1, Yuge Hou1,2, Takashi Yasuda3

  • 1Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba Meguro-Ku, Tokyo 153-8505, Japan.

JACS Au
|March 27, 2026
PubMed

Insights

Antimicrobial peptides (AMPs) like LL-37 and HNP-1 can reduce host-cell toxicity when they aggregate. This aggregation state is key to their function, impacting both cell death and survival pathways.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Antimicrobial peptides (AMPs) are crucial for innate immunity.
  • Synergistic effects of AMPs on bacterial killing are well-documented.
  • The impact of AMPs on host-cell cytotoxicity and the role of aggregation are less understood.

Purpose of the Study:

  • To investigate how heteroaggregation of human cathelicidin (LL-37) and human α-defensin-1 (HNP-1) affects host-cell cytotoxicity.
  • To determine the specific stoichiometric ratios governing the cooperative effects of LL-37 and HNP-1.
  • To elucidate the mechanisms underlying the modulation of cytotoxicity by AMP heteroaggregation.

Main Methods:

  • Dynamic light scattering (DLS) for aggregation analysis.
  • MTT assays and live/dead staining for cytotoxicity assessment.
  • Fluo-3 calcium imaging, apoptosis/necrosis assays, and ROS detection.
  • Optical and atomic force microscopy for structural visualization.

Main Results:

  • Cooperative reduction of MDCK-I cell cytotoxicity by LL-37 and HNP-1 occurs at a specific stoichiometric ratio (approx. 0.025 HNP-1 to LL-37).
  • Mutual antagonism between LL-37 and HNP-1 was observed, modulating cell death pathways.
  • HNP-1 suppressed LL-37-induced necrosis, while LL-37 reduced HNP-1-induced apoptosis.

Conclusions:

  • Heteroaggregation state is a critical determinant of AMPs' structure-function relationship.
  • AMP aggregation influences their ability to reduce host-cell cytotoxicity.
  • Understanding AMP aggregation provides insights into their dual role in host defense and potential toxicity.
Keywords:
antimicrobial peptidesdouble cooperativityheteroaggregationhuman cathelicidinhuman defensin

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