The Human Cathelicidin LL-37 Host Defense Peptide Upregulates Tight Junction-Related Proteins and Increases Human Epidermal Keratinocyte Barrier Function

Abstract

Both psoriasis and atopic dermatitis (AD) are not only associated with an impaired stratum corneum barrier, but also with abnormal expression of the tight junction (TJ) proteins. Because host defense peptides, including LL-37, are overexpressed in lesional psoriatic skin but are downregulated in lesional AD skin, we hypothesized that LL-37 might regulate the TJ function in keratinocytes. We demonstrated that LL-37 selectively increased the expression of several claudins and occludin, and enhanced their membrane distribution. Furthermore, LL-37 elevated the transepithelial electrical resistance while reducing the paracellular permeability of keratinocyte layers, and this activity was weakened by the claudin inhibitor ochratoxin A. A characterization of the molecular mechanism underlying the regulation of the TJ barrier by LL-37 revealed that LL-37 induced the activation of the Rac1, atypical PKC, glycogen synthase kinase-3 and PI3K pathways, and the specific inhibition of these pathways reversed the LL-37-mediated regulation of TJ function. In addition, LL-37 enhanced the expression of differentiation markers under the control of ochratoxin A, suggesting an association between LL-37-induced TJ function and keratinocyte differentiation. These data provide novel evidence that, in addition to its antimicrobial and other immunoregulatory functions, LL-37 contributes to cutaneous immunity by strengthening the skin's barrier function.

Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses

“…In this regard, it is notable that TRAF3IP2 silencing markedly inhibits the expression of ZC3H12A (Figures 4 and 5), which might be expected to relax this negative feedback regulation. While further studies are needed to understand the mechanistic function of TRAF3IP2 in keratinocyte's differentiation as well as the complex role of the Act1D10N mutation in keratinocytes with respect to the pathogenesis of psoriasis, our findings concur with others linking the processes of late keratinocyte differentiation and host defense (Akiyama et al, 2014, Gutowska-Owsiak et al, 2012), and suggest a role for TRAF3IP2 in the integration of these processes.…”

IL-1β–Induced Protection of Keratinocytes against Staphylococcus aureus-Secreted Proteases Is Mediated by Human β-Defensin 2

“…Alternatively, hBD2 may induce keratinocyte production of anti-proteases, TJ proteins other than claudin-1, or alternative factors. Recent studies have shown that exposure to high concentrations of exogenously applied hBD3 and LL-37 can selectively increase keratinocyte expression of claudins and occludin to enhance TJ function (Akiyama et al., 2014, Kiatsurayanon et al., 2014). However, in keeping with our study, hBD2 was found not to enhance TJ function, and the consequence of these HDP-mediated effects on susceptibility to bacterial proteases was not determined.…”

Friends or Foes? Host defense (antimicrobial) peptides and proteins in human skin diseases

“…In addition, both S100A7 and S100A8/S100A9 induce keratinocyte differentiation, and S100A8/S100A9 complex suppresses keratinocyte proliferation, indicating that S100A proteins act as regulators of epidermal differentiation and proliferation, which are the major characteristics of psoriasis pathogenesis. Furthermore, given that the skin TJ barrier is dysfunctional in the early events of psoriasis development and that hBD‐3, LL‐37 and S100A7 strengthen the TJ barrier in keratinocytes, AMPs/HDPs may play a key role in the TJ barrier defect observed in psoriasis.…”

“…AMPs represent one of the first evolved defense mechanisms, contributing to both innate and adaptive immune responses. In addition to their killing activities, AMPs display immunomodulatory properties, including induction of cell migration, proliferation and differentiation; regulation of cytokine/chemokine production; promotion of angiogenesis and wound healing; and maintenance of the barrier function of the skin (Table ) . Because AMP‐mediated immunomodulatory activities are even greater than the initially characterized antimicrobial activities, some investigators have proposed alternative names such as host defense peptide (HDP) or alarmin to describe these molecules …”