LL-37 secreted by epithelium promotes fibroblast collagen production: a potential mechanism of small airway remodeling in chronic obstructive pulmonary disease

Abstract

Emerging evidence suggests that the process of small airway remodeling is mediated by profibrotic growth factors produced by epithelium, which are capable of activating the underlying mesenchymal cells with excessive collagen production. It has been demonstrated that human cathelicidin antimicrobial protein LL-37 is highly expressed in small airway epithelium from COPD patients. However, it is unknown whether the increased levels of LL-37 in epithelium are involved in the pathogenesis of small airway remodeling in COPD. In this study, we examined the expression of LL-37 in small airways from smokers with COPD and controls (non-smokers and smokers without COPD) by immunohistochemistry, and then the association between LL-37 expression in epithelium and the structural changes of small airway remodeling was analyzed. In vitro, the effect of CSE-induced epithelial secretion of LL-37 on collagen production in human lung fibroblasts (HFL-1 cell line) was studied in a co-culture system. Finally, the signaling pathways involved in the effect of LL-37 on fibroblast collagen production were evaluated. The results showed that LL-37 immunoreactivity in airway epithelium was significantly elevated in smokers with COPD compared with controls. In addition, the magnitude of LL-37 expression in epithelium was positively correlated with airway wall thickness and collagen deposition. In vitro, CSE-induced epithelial secretion of LL-37 promoted fibroblast collagen production. Finally, we showed that formyl peptide receptor-like 1 (FPRL1)-dependent extracellular signal-regulated kinase (ERK) signaling pathway was essential for LL-37-induced collagen production in HFL-1 cells. These results suggest that after cigarette smoke exposure, the increased levels of LL-37 in airway epithelium could stimulate collagen production in the underlying lung fibroblasts and may contribute to small airway remodeling in COPD.

Antifibrogenic Effects of the Antimicrobial Peptide Cathelicidin in Murine Colitis-Associated Fibrosis

“… 26 Another putative cathelicidin receptor formyl peptide receptor-like 1 (FPRL1) was found to mediate LL-37-induced collagen production in human lung fibroblasts. 27 However, the antifibrogenic effect of LL-37 in human intestinal fibroblasts was not altered by pretreatment with the FPRL1 antagonist WRW4 or the P2X7 antagonist KN62 (data not shown), suggesting that the antifibrogenic effects of cathelicidin do not depend on these two putative cathelicidin receptors.…”

Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing

“…Mice lacking cathelicidin antimicrobial peptides are more susceptible to infection (Nizet et al, 2001), and qualitative defects in cathelicidin expression or activity play a role in the increased infection rates of humans with cystic fibrosis (Goldman et al, 1997), morbus Kostmann (Pütsep et al, 2002), and chronic vitamin D deficiency (Liu et al, 2006). Conversely, dysregulated and excessive levels of cathelicidin expression can be damaging to the host and a driver of diseases such as rosacea (Yamasaki et al, 2007), hidradenitis suppurativa (Emelianov et al, 2012), and cigarette smoke-associated chronic obstructive pulmonary disease (Sun et al, 2014). Cathelicidin expression may be limited because of these proinflammatory liabilities to levels for which resistance by pathogens is possible.…”

YKL-40 expression in chronic obstructive pulmonary disease: relation to acute exacerbations and airway remodeling

“…Airway remodeling is another prominent pathophysiologic feature of COPD, which is characterized by thickening of the airway wall with increased collagen deposition [ 16 ]. The mechanisms underlying its development have not been fully elucidated.…”