The study shows that a lung protein called SP‑A (and a lab‑made piece of it) can latch onto the human antimicrobial peptide LL‑37, stopping it from hurting lung cells and causing inflammation, while still letting it kill bacteria. This means LL‑37’s harmful side‑effects can be tamed by SP‑A, but the protein isn’t something you can easily take yourself yet.

Human cathelicidin (LL-37) is a defense peptide with antimicrobial activity against various pathogens. However, LL-37 can also trigger tissue injury by binding to host cell membranes. The cytotoxic effects of LL-37 may be especially relevant in chronic respiratory diseases characterized by increased LL-37. The aim of this study was to investigate whether the human collectin SP-A and a trimeric recombinant fragment thereof (rfhSP-A) can regulate the activities of LL-37. To this end, we studied the interaction of LL-37 with SP-A and rfhSP-A by intrinsic fluorescence, dynamic light scattering, and circular dichroism, as well as the effects of these proteins on the antimicrobial and cytotoxic activities of LL-37. Both SP-A and rfhSP-A bound LL-37 with high affinity at physiological ionic strength (<i>K_D</i> = 0.45 &#xb1; 0.01 nM for SP-A and 1.22 &#xb1; 0.7 nM for rfhSP-A). Such interactions result in the reduction of LL-37-induced cell permeability and IL-8 release in human pneumocytes, mediated by P2X7 channels. Binding of LL-37 to SP-A did not modify the properties of SP-A or the antibacterial activity of LL-37 against respiratory pathogens (<i>Klebsiella pneumoniae</i>, <i>Pseudomonas aeruginosa</i>, and nontypeable <i>Haemophilus influenzae</i>). SP-A/LL-37 complexes showed a greater ability to aggregate LPS vesicles than LL-37, which reduces endotoxin bioactivity. These results reveal the protective role of native SP-A in controlling LL-37 activities and suggest a potential therapeutic effect of rfhSP-A in reducing the cytotoxic and inflammatory actions of LL-37, without affecting its microbicidal activity against Gram-negative pathogens.