Antimicrobial Peptides and Systemic Inflammation: A Network Analysis

Abstract Antimicrobial peptides (AMPs) are essential components of the innate immune system, exhibiting diverse mechanisms of action. This study investigates the roles of cathelicidin (LL-37), alpha-defensins, and the S100 proteins S100A8 and S100A9 in systemic inflammation associated with sepsis, severe COVID-19, and acute pancreatitis using whole-blood bulk RNA-sequencing data. Gene co-expression network analysis revealed that during septic shock and severe COVID-19, cathelicidin and alpha-defensins act synergistically in innate immune responses, while S100A8 and S100A9 function through distinct pathways related to mitochondrial metabolism and ubiquitin ligase binding. In contrast, the acute pancreatitis network displayed a different pattern, with CAMP co-expressed alongside S100A8 and S100A9 , whereas alpha-defensins were downregulated and associated with inhibited mucosal immune responses. These findings suggest that antimicrobial peptides contribute variably to systemic inflammation depending on the underlying insult, underscoring their complex, context-dependent roles in critical illness.