Cathelicidin LL-37: A new important molecule in the pathophysiology of systemic lupus erythematosus

Abstract

Cathelicidin LL-37 is an antimicrobial peptide that is synthesized by epithelial cells, neutrophils, or lymphocytes and act as an essential defense mechanism against bacterial, viral, or fungi infection of eukaryotic organisms. However, in recent years, this cathelicidin has gained the interest of the scientific community because, besides its antimicrobial properties, LL-37 is an immunomodulator that can contribute to the development of autoimmune diseases. The other non-antimicrobial function of this cathelicidin is its ability to form complexes with the DNA, stimulating plasmacytoid dendritic cells (pDCs) to produce type I IFN, deciding the course of autoimmune diseases, including systemic lupus erythematosus (SLE). The chronic activation of pDCs by surrounding complexes is a crucial factor for the early development of autoimmunity in SLE patients. This stimulation is given by the complexes (LL-37-DNA/anti-DNA) recognized by the receptor FcγRII on pDCs, allowing its endocytosis and its recognition via TLR9, leading to the activation of pDCs and enhanced type I IFN production. In this article, we reviewed the structure, function, and importance of LL-37 in innate immunity, as well as its biological plausibility in the pathophysiology of autoimmune diseases such as SLE. In this narrative review, we included primary journal articles describing the function, structure, prevalence, and importance of LL-37 in various manifestations of SLE, as well as LL-37 and anti-LL37 antibodies in patients with SLE or other autoimmune diseases. In conclusion, LL-37 is an essential molecule in the pathophysiology of SLE, mainly by its role in increasing the production of IFN by pDCs, which postulates it as a crucial molecule in the pathophysiology of SLE and, given plausibility biology, could serve as a biomarker of the disease.

Cathelicidin – A Novel Potential Marker of Pediatric Inflammatory Bowel Disease

“… 25 Following stimulation by self-RNA released from necrotic cells, TLR3-mediated intracellular signaling pathway induces cathelicidin expression in colonic subepithelial myofibroblasts. 14 , 25 Expression of cathelicidin is also activated by vitamin D3, endoplasmic reticulum stress, IFNγ, TNFα, phenyl butyrate, and sodium butyrate. 12 …”

“… 39 Persistent expression of antimicrobial proteins may cause loss of tolerance to self-nucleic acids by the host, contributing to the development of autoimmune diseases. 14 , 39 Defective expression or altered function of cathelicidin may also lead to dysbiosis and loss of tolerance to commensal microbiota which is considered as a critical element in the pathogenesis of IBD. 12 , 39 …”

“… 8–10 Cathelicidin LL-37 is encoded as an inactive precursor by the CAMP gene which is located on the short arm of chromosome 3 (3p21.3). 13 , 14 Pre-protein hCAP18 is cleaved extracellularly by proteinase-3 to cathelicidin. 13 , 15 , 16 …”

“… 14 , 18 , 19 Recent research has revealed the role of cathelicidin in the pathophysiology of systemic lupus erythematosus, rheumatoid arthritis and psoriasis. 14 , 21 , 22 However, data on its implications in the development of inflammatory bowel disease are scarce. 23–26 To the best of our knowledge there is no study regarding cathelicidin in pediatric IBD.…”

Autoantibodies in psoriatic arthritis: are they of pathogenic relevance?

“…Increasing evidence suggests the direct involvement of autoantibodies against LL-37 in the pathogenesis of PsA. Moreover, anti-LL-37 antibodies in systemic lupus erythematosus have been proposed to activate neutrophils such that LL-37 is released via extracellular trap formation, after which LL-37 and DNA complexes are formed that trigger pDCs to produce type I interferon [ 27 ] ; a similar mechanism by anti-LL-37 is yet to be demonstrated in the pathogenesis of PsA.…”