Clarithromycin increased LL-37 antimicrobial peptide loading on neutrophil extracellular traps in type 2 diabetes patients, restoring antibacterial activity and promoting wound healing in lab tests.
LL-37 antibacterial function restoredClarithromycin increased LL-37 on diabetic neutrophil traps, restoring their ability to kill E. coli and promoting fibroblast-mediated wound healing
What the researchers found
Neutrophil extracellular traps (NETs) from type 2 diabetes patients contained LL-37 but lacked antibacterial activity compared to healthy controls. Key findings:
- NETs from both treatment-naive hyperglycemic and well-controlled diabetic patients failed to kill E. coli effectively
- Clarithromycin significantly increased LL-37 externalization on NETs from well-controlled diabetic patients
- This restored NET antibacterial capacity against E. coli
- Clarithromycin-enhanced NETs promoted wound healing by activating and differentiating primary skin fibroblasts
- The effect required well-controlled blood sugar (normoglycemic T2D patients), not treatment-naive hyperglycemic patients
Why it matters
Diabetic foot ulcers and wound infections are major complications that can lead to amputations. Understanding that the antimicrobial peptide LL-37 is deficient on diabetic NETs — and that clarithromycin can restore it — opens a new therapeutic strategy. This dual benefit of infection control and wound healing promotion through a single peptide pathway could significantly improve diabetic wound management.
How the study worked
Peripheral blood neutrophils were isolated from three groups: treatment-naive hyperglycemic T2D patients, normoglycemic well-controlled T2D patients, and healthy controls. NET release and LL-37 content were studied. Co-culture systems tested NETs against E. coli for antibacterial activity and with primary skin fibroblasts for wound healing. Clarithromycin's effects were assessed. Analysis used immunofluorescence confocal microscopy, ELISA, immunoblotting, and qRT-PCR.
What this study cannot tell us
This was an in vitro study — the effects of clarithromycin on LL-37 and wound healing were demonstrated in cell culture, not in living patients. The sample size of each patient group was not specified in the abstract. The wound healing assessment used fibroblast co-cultures, which is a simplified model of the complex in vivo wound environment. Clinical trials would be needed to confirm therapeutic benefit in diabetic patients.
How to read the evidence
This is an in vitro human cell study using neutrophils from diabetic patients and healthy controls. While it uses human cells and provides mechanistic insights, the clinical relevance needs to be confirmed through in vivo studies and clinical trials.
When this study was published
Published in 2018, this study contributes to the growing understanding of antimicrobial peptide dysfunction in diabetes and potential therapeutic interventions.
The bigger picture
LL-37 is the only human cathelicidin antimicrobial peptide and plays critical roles in innate immunity and tissue repair. This study reveals that diabetes impairs LL-37 function on immune cell traps, contributing to the infection susceptibility and poor wound healing seen in diabetic patients. The finding that an existing antibiotic can restore this peptide pathway represents a potential paradigm shift from using clarithromycin purely for its antibiotic properties to leveraging its immunomodulatory effects.
Questions still open
- Would topical or systemic clarithromycin treatment improve wound healing outcomes in diabetic patients through this LL-37 mechanism?
- Could direct LL-37 peptide therapy be more effective than clarithromycin-mediated indirect enhancement for diabetic wound care?
- Why did clarithromycin only restore LL-37 function in well-controlled but not in hyperglycemic diabetic patients?
Common questions
What is LL-37 and why is it important in diabetes?
Could clarithromycin help diabetic wounds heal better?
Read the original research
Clarithromycin Enhances the Antibacterial Activity and Wound Healing Capacity in Type 2 Diabetes Mellitus by Increasing LL-37 Load on Neutrophil Extracellular Traps.
Frontiers in immunology, 9, 2064
Citation
Arampatzioglou, Athanasios; Papazoglou, Dimitrios; Konstantinidis, Theocharis; Chrysanthopoulou, Akrivi; Mitsios, Alexandros; Angelidou, Iliana; Maroulakou, Ioanna; Ritis, Konstantinos; Skendros, Panagiotis. (2018). Clarithromycin Enhances the Antibacterial Activity and Wound Healing Capacity in Type 2 Diabetes Mellitus by Increasing LL-37 Load on Neutrophil Extracellular Traps.. Frontiers in immunology, 9, 2064. https://doi.org/10.3389/fimmu.2018.02064