The Role and Therapeutic Potential of Host Defense Peptides - The Innate Immune Effects of Cationic Host Defense Peptides

The Role and Therapeutic Potential of Host Defense Peptides - The Innate Immune Effects of Cationic Host Defense Peptides

Hancock, R. E. W., & Sahl, H.-G. (2006). Cationic host defence peptides: novel antimicrobial strategies against old and new pathogens. Nature Reviews Drug Discovery, *5*(2), 123–130. https://doi.org/10.1038/nrd2201
 

The primary role of natural cationic peptides in host defense has become increasingly compelling. While these peptides are involved in direct antimicrobial activity, their concentrations in many parts of the body (e.g., mucosal surfaces) are inconsistent with the levels required for direct antimicrobial (killing) effects. Recent data suggest that these peptides play a significant role in coordinating innate immunity. Indeed, their functions include mediating protection against endotoxic shock, promoting wound healing, stimulating chemokine synthesis and mast cell chemotaxis, enhancing angiogenesis, and exhibiting adjuvant activity in adaptive immune responses, as demonstrated in uninfected animal models. Notably, the effects of these host defense peptides are relatively novel, encompassing both anti-inflammatory and pro-inflammatory responses. Unlike typical innate immune responses, these peptides can resolve infections even while suppressing pro-inflammatory cytokines. 

Growing evidence now suggests that the immunomodulatory activities of cationic peptides are more significant than direct killing. These activities are expected to exert substantial qualitative effects on innate immune responses and inflammation, although they have only been roughly demonstrated experimentally and not fully validated in vivo. These activities include: (a) direct chemokine activity in recruiting neutrophils, monocytes, mast cells, and T-helper cells, as well as the ability to induce the production and release of neutrophil and monocyte chemokines from host cells, leading to the recruitment of innate immune cells to infection sites; (b) promoting mast cell degranulation, resulting in histamine release and subsequent vasodilation (increasing vascular permeability to various cells and proteins); (c) promoting dendritic cell differentiation, thereby altering the function of these cells; (d) enhancing phagocytosis; (e) inhibiting fibrin clot dissolution through tissue plasminogen activation, which may reduce bacterial dissemination; (f) promoting tissue and wound repair by enhancing fibroblast chemotaxis and growth; and (g) stimulating angiogenesis in endothelial cells, among others. It is well known that bacterial molecules such as LPS and lipoteichoic acid (LTA) stimulate innate immunity by interacting with Toll-like receptors. Notably, cationic host defense peptides actually inhibit LPS/LTA-stimulated production of pro-inflammatory cytokines such as TNFα and IL-6. As is the case with many responses in vitro and in vivo that require cationic peptides, defense peptides induce the expression of hundreds of genes in innate immune cells, including monocytes/macrophages and epithelial cells. 

To confirm the therapeutic potential of these findings, we constructed peptides lacking direct antimicrobial activity. Despite this, these peptides were able to protect mice from infections caused by Gram-positive (Staphylococcus aureus) and Gram-negative (Salmonella typhimurium) bacteria, indicating that they promote innate immunity.