Citrullination Modifies LL-37's Inflammatory Role in Human Airway Cells
Background
The human antimicrobial peptide LL-37 plays a crucial role in innate immunity, but its dysregulation is implicated in chronic inflammatory respiratory diseases like asthma and COPD. Citrullination, a post-translational modification, can alter protein function. While LL-37 is known to induce inflammatory responses, the specific impact of its citrullinated form on lipid mediators (oxylipins) and chemokine signaling in the airways has been unclear. This study addresses how citrullination affects LL-37's ability to enhance oxylipins and modulate COX-2-dependent chemokine responses in human bronchial epithelial cells.
Results
Both LL-37 and citrullinated-LL-37 significantly enhanced the production of various oxylipins, with LL-37 increasing total oxylipin levels by ~2.5-fold (p<0.01) and citrullinated-LL-37 by ~2.1-fold (p<0.05) compared to untreated controls. However, a key difference emerged in chemokine responses. Citrullination significantly attenuated the LL-37-mediated increase in inflammatory chemokines, reducing IL-8 and CCL2 secretion by approximately 62.5% (p<0.001) compared to native LL-37 treatment. Specifically, LL-37 treatment led to a 40% increase in IL-8 and CCL2 chemokine secretion, while citrullinated-LL-37 resulted in only a 15% increase. This attenuation was found to be largely COX-2-dependent, as pre-treatment with a COX-2 inhibitor abolished the remaining chemokine response induced by both peptide forms.
Why It Matters
This study highlights that citrullination can profoundly alter the inflammatory potential of LL-37, a crucial antimicrobial peptide. The finding that citrullinated LL-37 reduces COX-2-dependent chemokine responses, despite still enhancing oxylipins, suggests a complex regulatory role. This mechanism could be critical in understanding the pathogenesis of chronic inflammatory lung diseases where LL-37 is often dysregulated. Modifying LL-37 through citrullination or developing peptide mimetics could offer a novel therapeutic strategy to dampen excessive inflammation in conditions like asthma or cystic fibrosis, potentially leading to new peptide-based drugs for respiratory inflammation.