The study shows that the natural antimicrobial peptide LL‑37 helps eye‑infecting fungi by making immune cells called neutrophils better at grabbing and destroying the fungus. In mice, more LL‑37 meant fewer fungi, clearer eyes, and better healing, and this effect relied on a specific receptor (CXCR2) and cell‑cleaning processes (autophagy).

<i>Aspergillus fumigatus</i> (<i>A. fumigatus</i>) is one of the common pathogens of fungal keratitis. Fungal growth and invasion cause excessive inflammation and corneal damage, leading to severe vision loss. Neutrophils are the primary infiltrating cells critical for fungal clearance. Cathelicidin [LL-37 in humans and cathelicidin-related antimicrobial peptide (CRAMP) in mice], a natural antimicrobial peptide, can directly inhibit the growth of many pathogens and regulate immune responses. However, the role of cathelicidin and its effect on neutrophils in <i>A. fumigatus</i> keratitis remain unclear. By establishing <i>A. fumigatus</i> keratitis mouse models, we found that cathelicidin was increased in <i>A. fumigatus</i> keratitis. It could reduce fungal loads, lower clinical scores, and improve corneal transparency. Restriction of CRAMP on fungal proliferation was largely counteracted in <i>CD18^-/-</i> mice, in which neutrophils cannot migrate into infected sites. When WT neutrophils were transferred into <i>CD18^-/-</i> mice, corneal fungal loads were distinctly reduced, indicating that neutrophils are vital for CRAMP-mediated resistance. Furthermore, cathelicidin promoted neutrophils to phagocytose and degrade conidia both <i>in vitro</i> and <i>in vivo</i>. CXC chemokine receptor 2 (CXCR2) was reported to be a functional receptor of LL-37 on neutrophils. CXCR2 antagonist SB225002 or phospholipase C (PLC) inhibitor U73122 weakened LL-37-induced phagocytosis. Meanwhile, LL-37 induced PLC &#x3b3; phosphorylation, which was attenuated by SB225002. SB225002 or the autophagy inhibitors Bafilomycin-A1 and 3-Methyladenine weakened LL-37-induced degradation of conidia. Transmission electron microscopy (TEM) observed that LL-37 increased autophagosomes in <i>Aspergillus</i>-infected neutrophils. Consistently, LL-37 elevated autophagy-associated protein expressions (Beclin-1 and LC3-II), but this effect was weakened by SB225002. Collectively, cathelicidin reduces fungal loads and improves the prognosis of <i>A. fumigatus</i> keratitis. Both <i>in vitro</i> and <i>in vivo</i>, cathelicidin promotes neutrophils to phagocytose and degrade conidia. LL-37/CXCR2 activates PLC &#x3b3; to amplify neutrophils' phagocytosis and induces autophagy to eliminate intracellular conidia.