Cathelicidin-Ka, the first frog-derived TLR2 and TLR4 agonist, induces macrophage activation and promotes inflammation

TLR-targeted immunotherapy represents a promising strategy for combating infectious diseases by initiating or enhancing protective antimicrobial immunity. Here, we identified the first frog-derived TLR2 and TLR4 agonist, Cathelicidin-Ka (Cath-Ka), from the skin of Kaloula pulchra. The presence of Cath-Ka significantly enhanced proliferation, cytokine production, polarization, chemotaxis, phagocytosis, and intracellular bacterial killing of macrophages and peritoneal cells by targeting TLR2 and TLR4, rather than other pattern recognition receptors, and subsequently activated the downstream MyD88-MAPKs pathway. Cath-Ka also promoted macrophage polarization towards the M1 rather than M2 phenotype, and its intraperitoneal injection significantly promoted the chemotaxis of pro-inflammatory monocytes/macrophages into the peritoneal cavity. Finally, the mutant of Cath-Ka with amination at C-terminus had stronger effects on macrophage function modulation than the original peptide. These findings suggest that Cath-Ka and its amidated mutant are promising candidates for the treatment of TLR2 and TLR4-related diseases, including infections.