title: LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection.
abstract: The human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro- and anti-inflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1α and tumor necrosis factor-α (TNF-α), which are induced by lipopolysaccharides (LPS). The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and mammalian target of rapamycin (mTOR). The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions.
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and technology, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Dermatology, The 2nd Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China. Electronic address: zenyan66@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and technology, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Zhuoyang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and technology, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and technology, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Dermatology, The 2nd Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Dermatology, The 2nd Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Department of Medicine, University of California Irvine Medical School, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California Irvine Medical School, Irvine, CA 92697, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and technology, Xi'an Jiaotong University, Xi'an 710049, China; Department of Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089-9121, USA. Electronic address: j.liu@mail.xjtu.edu.cn.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012871:Skin Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D012333:RNA, Messenger; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D054804:Cathelicidins
keywords: HaCaT cells; Inflammation; LL-37; Mitochondrion; mTOR