Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not proinflammatory to phagocytosing macrophages

Abstract

Cathelicidins are CHDP with essential roles in innate host defense but also more recently associated with the pathogenesis of certain chronic diseases. These peptides have microbicidal potential and the capacity to modulate innate immunity and inflammatory processes. PMN are key innate immune effector cells with pivotal roles in defense against infection. The appropriate regulation of PMN function, death, and clearance is critical to innate immunity, and dysregulation is implicated in disease pathogenesis. The efferocytosis of apoptotic PMN, in contrast to necrotic cells, is proposed to promote the resolution of inflammation. We demonstrate that the human cathelicidin LL-37 induced rapid secondary necrosis of apoptotic human PMN and identify an essential minimal region of LL-37 required for this activity. Using these LL-37-induced secondary necrotic PMN, we characterize the consequence for macrophage inflammatory responses. LL-37-induced secondary necrosis did not inhibit PMN ingestion by monocyte-derived macrophages and in contrast to expectation, was not proinflammatory. Furthermore, the anti-inflammatory effects of apoptotic PMN on activated macrophages were retained and even potentiated after LL-37-induced secondary necrosis. However, this process of secondary necrosis did induce the release of potentially harmful PMN granule contents. Thus, we suggest that LL-37 can be a potent inducer of PMN secondary necrosis during inflammation without promoting macrophage inflammation but may mediate host damage through PMN granule content release under chronic or dysregulated conditions.

The Human Cathelicidin LL-37 Has Antiviral Activity against Respiratory Syncytial Virus

“…In vivo modelling is required to evaluate the efficacy of such an approach, but the observation that antiviral activity is retained by a truncated peptide demonstrates the potential to develop shorter synthetic analogues for future testing. Interestingly, our evaluation of these previously characterised [24] partial peptides representing the N-terminus (amino acids 1–22), a central portion (amino acids 12–33) and the C-terminus (amino acids 16–37) of LL-37 suggests that the antiviral activity may relate to the same core peptide region previously identified for antibacterial activity [24], [40] and for the capacity to induce secondary necrosis of apoptotic cells [41].…”

Carbamylated LL-37 as a modulator of the immune response

“…Intriguingly, the ability of LL-37 C8 and LL-37 C12,15 to lyse neutrophils and erythrocytes was different. Neutrophil membranes are zwitterionic and interact with LL-37 independently of the overall charge of the peptide [22,39]. By contrast, the erythrocyte membrane contains sialic acid, which results in a negatively charged cell surface; therefore, it is more susceptible to lysis by cationic peptides.…”

“…Finally, recent studies show that LL-37 has a direct effect on the cells and might be hemolytic [20] or cytotoxic to peripheral blood mononuclear cells (PBMCs) at high concentrations [21]. At low concentrations (<5 μM), LL-37 induces rapid secondary necrosis of apoptotic human neutrophils [22]. To prevent collateral tissue damage due to exacerbation of inflammation, the activity of LL-37 is strictly controlled by serum proteins [23], most likely apolipoprotein-A1 (apoA-1) [24].…”

Human cathelicidin LL‐37 and its derivative IG‐19 regulate interleukin‐32‐induced inflammation

“…The role of LL‐37 to regulate pathogen‐induced inflammation is now well established . In addition, recent studies have also demonstrated that partial fragments of LL‐37, including the peptide IG‐19, can suppress bacterial endotoxin‐induced inflammatory cytokines . However, the role of LL‐37 and its derivatives in regulating sterile inflammation has not been well defined.…”