LL-37 Exacerbates Local Inflammation in Sepsis-Induced Acute Lung Injury by Preventing Mitochondrial DNA (mtDNA) Degradation-Induced Autophagy

Abstract

BackgroundRecent studies have proved that autophagy dysfunction in proinflammatory cells is involved in tissue damage and an excessive inflammatory response in sepsis. In the present study, we identified that the human antimicrobial peptide LL-37 facilitates resistance to DNase II-induced mitochondrial DNA (mtDNA) degradation and subsequent autophagy.Material/MethodsWe found higher serum levels of LL-37 in patients with severe sepsis compared to that in patients with mild sepsis. Neutrophils isolated from mice with sepsis after treatment with Cramp-mtDNA produced an excess of proinflammatory cytokines, including IL-1β, IL-6, IL-8, MMP-8, and TNF-α. Cramp-mtDNA in the lung samples from model animals with sepsis was detected by immunohistochemical staining.ResultsExogenous delivery of Cramp-mtDNA complex significantly exacerbated lung inflammation but the antibody against Cramp-mtDNA attenuated the excessive inflammatory response in LPS-induced acute lung injury. The expression of proinflammatory cytokines in lungs was upregulated and downregulated after treatment with the complex and antibody, respectively. LC-3 expression in 16HBE cells increased after LPS induction, irrespective of stimulation with LL-37.ConclusionsThese data show that LL-37 treatment worsens local inflammation in sepsis-induced acute lung injury by preventing mtDNA degradation-induced autophagy.

Between good and evil: Complexation of the human cathelicidin LL-37 with nucleic acids

“…Antibody treatment targeting the LL-37-mtDNA complex mitigated lesion formation, leading the authors to conclude that the complexes drive atherosclerotic plaque formation, and disruption of these complexes may offer strategies for atherosclerosis prevention and treatment ( 32 ). By preventing mtDNA degradation-induced autophagy, another study showed that LL-37-mtDNA complexes aggravate local inflammation in sepsis-induced acute lung injury ( 64 ). Just as in the atherosclerosis study, elevated levels of LL-37 in serum were found in severe sepsis patients compared with individuals with mild sepsis.…”

Old and new damage‐associated molecular patterns (DAMPs) in autoimmune diseases

“…By injecting mice with mtDNA, neutrophils are activated via p38 MAPK to produce excess proinflammatory cytokines, including IL-1β, IL-6, IL-8, MMP-8, and TNF-α, and induce inflammation. 73,74 To date, mtDNA functions in adaptive immunity have been rarely reported. T-cell receptor (TCR) activation triggers mtDNA production.…”

“…Similar studies have confirmed the inflammatory nature of mtDNA by demonstrating that mtDNA directly activates various pattern recognition receptors to trigger an inflammatory response. By injecting mice with mtDNA, neutrophils are activated via p38 MAPK to produce excess proinflammatory cytokines, including IL‐1β, IL‐6, IL‐8, MMP‐8, and TNF‐α, and induce inflammation 73,74 …”

Diagnostic value of miR-155 for acute lung injury/acute respiratory distress syndrome in patients with sepsis

“… 4 In the case of sepsis, various inflammatory factors and mediators are released and activated in large quantities, and the imbalance between inflammatory and anti-inflammatory factors damages lung tissue and promotes the development of ALI/ARDS. 5 …”

“…4 In the case of sepsis, various inflammatory factors and mediators are released and activated in large quantities, and the imbalance between inflammatory and anti-inflammatory factors damages lung tissue and promotes the development of ALI/ARDS. 5 Identifying new biomarkers of ALI/ ARDS for early diagnosis and treatment is an important approach to improve the prognosis of patients with sepsis. Studies on the relationship between microRNAs (miRNAs) and tumors have become a hot topic in the medical community.…”