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1.  Structure and function of the human skin microbiome 
Trends in microbiology  2013;21(12):660-668.
An abundant and diverse collection of bacteria, fungi and viruses inhabit the human skin. These microorganisms have been reported to vary between individuals and between different sites on the skin. The factors responsible for the unique variability of the skin microbiome are only partially understood, but results suggest host genetic and environmental influences play a major role. Today, the steady accumulation of data describing the skin microbiome, combined with experiments designed to test the biological functions of surface microbes, have provided new insights into links between human physiology and skin microbiota. This review describes some of the current information regarding the skin microbiome and their impact on human health. Specifically, this review seeks to summarize the present understanding of the function of microbe–host interactions on the skin and highlight some unique features that distinguish skin commensals from pathogenic microbes.
doi:10.1016/j.tim.2013.10.001
PMCID: PMC4744460  PMID: 24238601
microbiota; microbial diversity; skin diseases; skin health
2.  Endogenous intracellular cathelicidin enhances TLR9 activation in dendritic cells and macrophages* 
Cathelicidins are a gene family best known for their antimicrobial action, but the diverse mature peptides they encode also have other host defense functions. The human cathelicidin peptide LL-37 enhances recognition of nucleic acids, an action whose significance is seen in human diseases such as psoriasis where it is associated with increased type-1 interferon production. This function has been attributed to the extracellular action of the peptide to facilitate uptake of nucleic acids. Here, we demonstrate that the murine mature cathelicidin peptide (CRAMP), encoded by the mouse gene (Camp), is functionally distinct from the human mature peptide (LL-37), as it does not facilitate CpG entry. However, mouse cathelicidin does influence recognition of CpG as bone marrow-derived dendritic cells (BMDCs) from Camp−/− mice have impaired CpG responses and Camp−/− mice had impaired response to CpG given intravenously or subcutaneously. We show that cathelicidin concentrates in Lamp1 positive compartments, is colocalized with CpG in the endolysosome, can be immunoprecipitated with TLR9, and binds to CpG intracellulary. Collectively, these results indicate that the functions of cathelicidin in control of TLR9 activation may include both intracellular and extracellular effects.
doi:10.4049/jimmunol.1402388
PMCID: PMC4297737  PMID: 25548223
3.  Toll-like receptor 3 activation is required for normal skin barrier repair following UV damage 
Ultraviolet (UV) damage to the skin leads to the release of noncoding RNA (ncRNA) from necrotic keratinocytes that activates toll-like receptor 3 (TLR3). This release of ncRNA triggers inflammation in the skin following UV damage. Recently, TLR3 activation was also shown to aid wound repair and increase expression of genes associated with permeability barrier repair. Here, we sought to test if skin barrier repair after UVB damage is dependent on the activation of TLR3. We observed that multiple ncRNAs induced expression of skin barrier repair genes, that the TLR3 ligand Poly (I:C) also induced expression and function of tight junctions, and that the ncRNA U1 acts in a TLR3-dependent manner to induce expression of skin barrier repair genes. These observations were shown to have functional relevance as Tlr3−/− mice displayed a delay in skin barrier repair following UVB damage. Combined, these data further validate the conclusion that recognition of endogenous RNA by TLR3 is an important step in the program of skin barrier repair.
doi:10.1038/jid.2014.354
PMCID: PMC4289479  PMID: 25118157
4.  Vaccinia virus binds to the scavenger receptor MARCO on the surface of keratinocytes 
Patients with altered skin immunity, such as individuals with atopic dermatitis (AD), can have a life-threatening disruption of the epidermis known as eczema vaccinatum (EV) after vaccinia virus (VV) infection of the skin. Here, we sought to better understand the mechanism(s) by which VV associates with keratinocytes. The class A scavenger receptor known as MARCO (macrophage receptor with collagenous structure) is expressed on human and mouse keratinocytes and found to be abundantly expressed in the skin of patients with AD. VV bound directly to MARCO, and overexpression of MARCO increased susceptibility to VV infection. Furthermore, ligands with affinity for MARCO, or excess soluble MARCO, competitively inhibited VV infection. These findings indicate that MARCO promotes VV infection and highlights potential new therapeutic strategies for prevention of VV infection in the skin.
doi:10.1038/jid.2014.330
PMCID: PMC4268046  PMID: 25089661
5.  Ultraviolet B radiation illuminates the role of TLR3 in the epidermis 
UV radiation poses a significant risk to human health. The mechanisms that help repair UV-damaged cells have recently been more clearly defined with the observation that Toll-like receptor 3 can sense self RNA released from necrotic keratinocytes following UV damage. TLR3 activation in the skin induces inflammation and increases expression of genes involved in skin barrier repair. Activation of TLR2 in the skin by commensal microbial products prevents excessive inflammation by blocking downstream TLR3 signaling. This review highlights how UV damage induced inflammation in the skin is propagated by host products and regulated by host inhabitants.
doi:10.1038/jid.2014.167
PMCID: PMC4133277  PMID: 24786223
6.  Anti-fibrogenic effects of the anti-microbial peptide cathelicidin in murine colitis-associated fibrosis 
Background and Aims
Cathelicidin (LL-37 in human and mCRAMP in mice) represents a family of endogenous antimicrobial peptides with anti-inflammatory effects. LL-37 also suppresses collagen synthesis, an important fibrotic response, in dermal fibroblasts. Here we determined whether exogenous cathelicidin administration modulates intestinal fibrosis in two animal models of intestinal inflammation and in human colonic fibroblasts.
Methods
C57BL/6J mice (n=6 per group) were administered intracolonically with a trinitrobenzene sulphonic acid (TNBS) enema to induce chronic (6–7 weeks) colitis with fibrosis. mCRAMP peptide (5 mg/kg every 3 day, week 5–7) or cathelicidin gene (Camp)-expressing lentivirus (107 infectious units week 4) were administered intracolonically or intravenously, respectively. 129Sv/J mice were infected with Salmonella typhimurium orally to induce cecal inflammation with fibrosis. Camp expressing lentivirus (107 infectious units day 11) was administered intravenously.
Results
TNBS-induced chronic colitis was associated with increased colonic collagen (col1a2) mRNA expression. Intracolonic cathelicidin (mCRAMP peptide) administration or intravenous delivery of lentivirus-overexpressing cathelicidin gene significantly reduced colonic col1a2 mRNA expression in TNBS-exposed mice, compared to vehicle administration. Salmonella infection also caused increased cecal inflammation associated with collagen (col1a2) mRNA expression that was prevented by intravenous delivery of Camp-expressing lentivirus. Exposure of human primary intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor-beta1 (TGF-beta1) and/or insulin-like growth factor 1 induced collagen protein and mRNA expression, that was reduced by LL-37 (3–5 µM) through a MAP kinase-dependent mechanism.
Conclusion
Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts.
doi:10.1016/j.jcmgh.2014.08.001
PMCID: PMC4338438  PMID: 25729764
Anti-microbial peptide; inflammatory bowel disease; collagen
7.  Etanercept decreases the innate immune wounding response in psoriasis 
Experimental dermatology  2013;22(9):599-601.
Cathelicidin is increased when normal skin is injured and in psoriasis lesions where it has been suggested to play a pivotal role in inflammation through interactions with self-DNA and toll-like receptor 9 (TLR-9) in keratinocytes and plasmacytoid dendritic cells. Because of etanercept’s success in treating psoriasis, we hypothesized that etanercept may suppress TLR-9 and cathelicidin induction. Examination of experimentally induced wounds of psoriatic lesional and non-lesional skin, and comparison with wounded normal skin, shows that the induction of cathelicidin and TLR-9 is greatly enhanced in lesional psoriatic skin. Six weeks of etanercept appears not to affect the baseline expression of cathelicidin or TLR-9, but does blunt the induction of cathelicidin in psoriasis with wounding. These findings support the role of cathelicidin in the enhancement of local inflammation in psoriasis and may partially explain one of the mechanisms enabling TNF-α inhibitors to successfully treat this disorder.
doi:10.1111/exd.12167
PMCID: PMC4195436  PMID: 23802569
cathelicidin; etanercept; psoriasis; TLR-9
8.  Doxycycline Indirectly Inhibits Proteolytic Activation of Tryptic Kallikrein-Related Peptidases and Activation of Cathelicidin 
The increased abundance and activity of cathelicidin and kallikrein 5 (KLK5), a predominant trypsin-like serine protease (TLSP) in the stratum corneum, have been implicated in the pathogenesis of rosacea, a disorder treated by the use of low-dose doxycycline. Here we hypothesized that doxycycline can inhibit activation of tryptic KLKs through an indirect mechanism by inhibition of matrix metalloproteinases (MMPs) in keratinocytes. The capacity of doxycycline to directly inhibit enzyme activity was measured in surface collections of human facial skin and extracts of cultured keratinocytes by fluorescence polarization assay against fluorogenic substrates specific for MMPs or TLSPs. Doxycycline did inhibit MMP activity but did not directly inhibit serine protease activity against a fluorogenic substrate specific for TLSPs. However, when doxycycline or other MMP inhibitors were added to live keratinocytes during the production of tryptic KLKs, this treatment indirectly resulted in decreased TLSP activity. Furthermore, doxycycline under these conditions inhibited the generation of the cathelicidin peptide LL-37 from its precursor protein hCAP18, a process dependent on KLK activity. These results demonstrate that doxycycline can prevent cathelicidin activation, and suggest a previously unknown mechanism of action for doxycycline through inhibiting generation of active cathelicidin peptides.
doi:10.1038/jid.2012.14
PMCID: PMC4169281  PMID: 22336948
9.  Beta-Lactamase Repressor BlaI Modulates Staphylococcus aureus Cathelicidin Antimicrobial Peptide Resistance and Virulence 
PLoS ONE  2015;10(8):e0136605.
BlaI is a repressor of BlaZ, the beta-lactamase responsible for penicillin resistance in Staphylococcus aureus. Through screening a transposon library in S. aureus Newman for susceptibility to cathelicidin antimicrobial peptide, we discovered BlaI as a novel cathelicidin resistance factor. Additionally, through integrational mutagenesis in S. aureus Newman and MRSA Sanger 252 strains, we confirmed the role of BlaI in resistance to human and murine cathelidicin and showed that it contributes to virulence in human whole blood and murine infection models. We further demonstrated that BlaI could be a target for innate immune-based antimicrobial therapies; by removing BlaI through subinhibitory concentrations of 6-aminopenicillanic acid, we were able to sensitize S. aureus to LL-37 killing.
doi:10.1371/journal.pone.0136605
PMCID: PMC4549145  PMID: 26305782
10.  Cathelicidin, kallikrein 5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel 
Background
Excess cathelicidin and kallikrein 5 (KLK5) have been hypothesized to play a role in the pathophysiology of rosacea.
Objective
We sought to evaluate the effects of azelaic acid (AzA) on these elements of the innate immune system.
Methods
Gene expression and protease activity were measured in laboratory models and patients with rosacea during a 16-week multicenter, prospective, open-label study of 15% AzA gel.
Results
AzA directly inhibited KLK5 in cultured keratinocytes and gene expression of KLK5, Toll-like receptor-2, and cathelicidin in mouse skin. Patients with rosacea showed reduction in cathelicidin and KLK5 messenger RNA after treatment with AzA gel. Subjects without rosacea had lower serine protease activity (SPA) than patients with rosacea. Distinct subsets of patients with rosacea who had high and low baseline SPA were identified, and patients with high baseline exhibited a statistically significant reduction of SPA with 15% AzA gel treatment.
Limitations
Study size was insufficient to predict clinical efficacy based on the innate immune response to AzA.
Conclusions
These results show that cathelicidin and KLK5 decrease in association with AZA exposure. Our observations suggest a new mechanism of action for AzA and that SPA may be a useful biomarker for disease activity.
doi:10.1016/j.jaad.2013.05.019
PMCID: PMC3910251  PMID: 23871720
antimicrobial peptides; azelaic acid; cathelicidin; kallikrein 5; LL-37; rosacea; serine protease
11.  Hyaluronan digestion controls DC migration from the skin 
The Journal of Clinical Investigation  2014;124(3):1309-1319.
The breakdown and release of hyaluronan (HA) from the extracellular matrix has been hypothesized to act as an endogenous signal of injury. To test this hypothesis, we generated mice that conditionally overexpressed human hyaluronidase 1 (HYAL1). Mice expressing HYAL1 in skin either during early development or by inducible transient expression exhibited extensive HA degradation, yet displayed no evidence of spontaneous inflammation. Further, HYAL1 expression activated migration and promoted loss of DCs from the skin. We subsequently determined that induction of HYAL1 expression prior to topical antigen application resulted in a lack of an antigenic response due to the depletion of DCs from the skin. In contrast, induction of HYAL1 expression concurrent with antigen exposure accelerated allergic sensitization. Administration of HA tetrasaccharides, before or simultaneously with antigen application, recapitulated phenotypes observed in HYAL1-expressing animals, suggesting that the generation of small HA fragments, rather than the loss of large HA molecules, promotes DC migration and subsequent modification of allergic responses. Furthermore, mice lacking TLR4 did not exhibit HA-associated phenotypes, indicating that TLR4 mediates these responses. This study provides direct evidence that HA breakdown controls the capacity of the skin to present antigen. These events may influence DC function in injury or disease and have potential to be exploited therapeutically for modification of allergic responses.
doi:10.1172/JCI67947
PMCID: PMC3934161  PMID: 24487587
12.  Activation of TLR3 in keratinocytes increases expression of genes involved in formation of the epidermis, lipid accumulation and epidermal organelles 
Injury to the skin, and the subsequent release of non-coding double-stranded RNA from necrotic keratinocytes, has been identified as an endogenous activator of Toll-like receptor 3 (TLR3). Since changes in keratinocyte growth and differentiation follow injury, we hypothesized that TLR3 might trigger some elements of the barrier repair program in keratinocytes. Double-stranded RNA was observed to induce TLR3-dependent increases in human keratinocyte mRNA abundance for ABCA12 (ATP-binding cassette, sub-family A, member 12), glucocerebrosidase, acid sphingomyelinase, and transglutaminase 1. Additionally, treatment with double-stranded RNA resulted in increases in sphingomyelin and morphologic changes including increased epidermal lipid staining by oil-red O and TLR3-dependent increases in lamellar bodies and keratohyalin granules. These observations show that double-stranded RNA can stimulate some events in keratinocytes that are important for skin barrier repair and maintenance.
doi:10.1038/jid.2013.39
PMCID: PMC3686920  PMID: 23353987
13.  Novel role of the antimicrobial peptide LL-37 in the protection of neutrophil extracellular traps against degradation by bacterial nucleases 
Journal of innate immunity  2014;6(6):860-868.
Neutrophil extracellular traps (NETs) have been described as a fundamental innate immune defense mechanism. These NETs consist of a nuclear DNA backbone associated with different antimicrobial peptides (AMPs), which are able to engulf and kill pathogens. The AMP LL-37, a member of the cathelicidin family, is highly present in NETs. However, the function of LL-37 within the NETs is still unknown, since LL-37 loses its antimicrobial activity when bound to DNA in the NETs.
Using immunofluorescence microscopy we demonstrate that NETs treated with LL-37 were distinctly more resistant to S. aureus nuclease degradation compared to non-treated NETs. Biochemical assays utilising a random LL-37-fragment library indicate that the blocking effect of LL-37 on nuclease activity is based on the cationic character of the AMP, which facilitates the binding to neutrophil DNA, thus protecting it from degradation by the nuclease. In good correlation to these data, the cationic AMPs human beta defensin-3 (hBD-3) and human neutrophil peptide-1 (HNP-1) showed similar protection of neutrophil-derived DNA against nuclease degradation. In conclusion, this study demonstrates a novel role of AMPs in host immune defence: Besides its direct antimicrobial activity against various pathogens, cationic AMPs can stabilise neutrophil-derived DNA or NETs against bacterial nuclease degradation.
doi:10.1159/000363699
PMCID: PMC4201878  PMID: 25012862
neutrophil extracellular traps (NETs); antimicrobial peptide; nuclease; cathelicidin; human neutrophil peptide-1 (HNP-1); human beta defensin 3 (hBD3)
14.  A randomized controlled double blind investigation of the effects of Vitamin D dietary supplementation in subjects with atopic dermatitis 
Background
Subjects with atopic dermatitis (AD) have defects in antimicrobial peptide (AMP) production possibly contributing to an increased risk of infections. In laboratory models, vitamin D can alter innate immunity by increasing AMP production.
Objective
To determine if AD severity correlates with baseline vitamin D levels, and to test whether supplementation with oral vitamin D alters AMP production in AD skin.
Methods
This was a multi-center, placebo controlled, double-blind study in 30 subjects with AD, 30 non-atopic subjects, and 16 subjects with psoriasis. Subjects were randomized to receive either 4000 IU of cholecalciferol or placebo for 21 days. At baseline and day 21, levels of 25-hydroxyvitamin D (25OHD), cathelicidin, HBD-3, IL-13, and Eczema Area and Severity Index (EASI) and Rajka-Langeland scores were obtained.
Results
At baseline, 20% of AD subjects had serum 25OHD below 20 ng/ml. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI, but not AD severity. After 21 days of oral cholecalciferol, mean serum 25OHD increased, but there was no significant change in skin cathelicidin, HBD-3, IL-13, or EASI scores.
Conclusions
This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD, and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels. Given the molecular links between vitamin D and immune function, further study of vitamin D supplementation in subjects with AD is warranted.
doi:10.1111/jdv.12176
PMCID: PMC3769441  PMID: 23638978
15.  L-Rhamnosylation of Listeria monocytogenes Wall Teichoic Acids Promotes Resistance to Antimicrobial Peptides by Delaying Interaction with the Membrane 
PLoS Pathogens  2015;11(5):e1004919.
Listeria monocytogenes is an opportunistic Gram-positive bacterial pathogen responsible for listeriosis, a human foodborne disease. Its cell wall is densely decorated with wall teichoic acids (WTAs), a class of anionic glycopolymers that play key roles in bacterial physiology, including protection against the activity of antimicrobial peptides (AMPs). In other Gram-positive pathogens, WTA modification by amine-containing groups such as D-alanine was largely correlated with resistance to AMPs. However, in L. monocytogenes, where WTA modification is achieved solely via glycosylation, WTA-associated mechanisms of AMP resistance were unknown. Here, we show that the L-rhamnosylation of L. monocytogenes WTAs relies not only on the rmlACBD locus, which encodes the biosynthetic pathway for L-rhamnose, but also on rmlT encoding a putative rhamnosyltransferase. We demonstrate that this WTA tailoring mechanism promotes resistance to AMPs, unveiling a novel link between WTA glycosylation and bacterial resistance to host defense peptides. Using in vitro binding assays, fluorescence-based techniques and electron microscopy, we show that the presence of L-rhamnosylated WTAs at the surface of L. monocytogenes delays the crossing of the cell wall by AMPs and postpones their contact with the listerial membrane. We propose that WTA L-rhamnosylation promotes L. monocytogenes survival by decreasing the cell wall permeability to AMPs, thus hindering their access and detrimental interaction with the plasma membrane. Strikingly, we reveal a key contribution of WTA L-rhamnosylation for L. monocytogenes virulence in a mouse model of infection.
Author Summary
Listeria monocytogenes is a foodborne bacterial pathogen that preferentially infects immunocompromised hosts, eliciting a severe and often lethal disease. In humans, clinical manifestations range from asymptomatic intestinal carriage and gastroenteritis to harsher systemic states of the disease such as sepsis, meningitis or encephalitis, and fetal infections. The surface of L. monocytogenes is decorated with wall teichoic acids (WTAs), a class of carbohydrate-based polymers that contributes to cell surface-related events with implications in physiological processes, such as bacterial division or resistance to antimicrobial peptides (AMPs). The addition of other molecules to the backbone of WTAs modulates their chemical properties and consequently their functionality. In this context, we studied the role of WTA tailoring mechanisms in L. monocytogenes, whose WTAs are strictly decorated with monosaccharides. For the first time, we link WTA glycosylation with AMP resistance by showing that the decoration of L. monocytogenes WTAs with l-rhamnose confers resistance to host defense peptides. We suggest that this resistance is based on changes in the permeability of the cell wall that delay its crossing by AMPs and therefore promote the protection of the bacterial membrane integrity. Importantly, we also demonstrate the significance of this WTA modification in L. monocytogenes virulence.
doi:10.1371/journal.ppat.1004919
PMCID: PMC4441387  PMID: 26001194
16.  HSV-1 exploits the innate immune scavenger receptor MARCO to enhance epithelial adsorption and infection 
Nature communications  2013;4:1963.
HSV-1 is an important epithelial pathogen and has the potential for significant morbidity in humans. Here we demonstrate that a cell surface scavenger receptor, macrophage receptor with collagenous structure (MARCO), previously thought to enhance antiviral defense by enabling nucleic acid recognition, is usurped by HSV-1 and functions together with heparan sulfate proteoglycans to mediate adsorption to epithelial cells. Ligands of MARCO dramatically inhibit HSV-1 adsorption and infection of human keratinocytes and protect mice against infection. HSV-1 glycoprotein C (gC) closely co-localizes with MARCO at the cell surface, and gC binds directly to purified MARCO with high affinity. Increasing MARCO expression enhances HSV-1 infection while MARCO-/- mice have reduced susceptibility to infection by HSV-1. These findings demonstrate that HSV-1 binds to MARCO to enhance its capacity for disease, and suggests a new therapeutic target to alter pathogenicity of HSV-1 in skin infection.
doi:10.1038/ncomms2963
PMCID: PMC3681428  PMID: 23739639
17.  Mast cells are key mediators of cathelicidin initiated skin inflammation in rosacea 
Rosacea is a chronic inflammatory skin disease whose pathophysiological mechanism is still unclear. However, it is known that mast cell (MC) numbers is increased in the dermis of rosacea patients. MC proteases not only recruit other immune cells, which amplify the inflammatory response, but also cause vasodilation and angiogenesis. MCs are also one of the primary sources of cathelicidin LL-37 (Cath LL-37), an antimicrobial peptide that has been shown to be an enabler of rosacea pathogenesis. Here, we demonstrate that MCs are key mediators of cathelicidin initiated skin inflammation. Following Cath LL-37 injection into the dermis, MC deficient B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh) mice did not develop rosacea-like features. Conversely, chymase (p<0.001), tryptase and Mmp9 (p<0.01) mRNA levels were significantly higher in C57BL/6 Wild Type (WT) mice. Treating WT mice with a MC stabilizer significantly decreased the expressions of Mmp9 and Cxcl2 (p<0.01). Our data was confirmed on Erythematotelangiectatic rosacea subjects that showed a decrease in MMP activity (p<0.05), after eight weeks of topical cromolyn treatment.
We conclude that MCs play a central role in the development of inflammation subsequent to Cath LL-37 activation and that down regulation of activated MCs may be a therapy for rosacea treatment.
doi:10.1038/jid.2014.222
PMCID: PMC4199909  PMID: 24844861
18.  Granulysin-Derived Peptides Demonstrate Antimicrobial and Anti-Inflammatory Effects Against Propionibacterium acnes 
Propionibacterium acnes is a key therapeutic target in acne, yet this bacterium has become resistant to standard antibiotic agents. We investigated whether the human antimicrobial protein granulysin is a potential candidate for the treatment of acne. Granulysin and synthetic granulysin-derived peptides possessing a helix–loop–helix motif killed P. acnes in vitro. Modification of a helix–loop–helix peptide, 31–50, by substitution of a tryptophan for the valine at amino acid 44 (peptide 31–50v44w) to increase its interaction with bacterial surfaces also increased its antimicrobial activity. Moreover, when synthesized with d- rather than l-type amino acids, this peptide (d-31– 50v44w) became less susceptible to degradation by proteases and more effective in killing P. acnes. Granulysin peptides were bactericidal, demonstrating an advantage over standard bacteriostatic antibiotics in their control of P. acnes. Moreover, peptide d-31–50v44w killed P. acnes in isolated human microcomedone preparations. Importantly, peptides 31–50, 31–50v44w, and d-31–50v44w also have potential anti-inflammatory effects, as demonstrated by suppression of P. acnes-stimulated cytokine release. Taken together, these data suggest that granulysin peptides may be useful as topical therapeutic agents, providing alternatives to current acne therapies.
doi:10.1111/j.0022-202X.2005.23805.x
PMCID: PMC4407689  PMID: 16098035
acne; antimicrobial peptide; inflammation; innate immunity; skin
19.  Antimicrobial peptides: Old Molecules with New Ideas 
The Journal of investigative dermatology  2011;132(3 0 2):887-895.
Almost 90 years have passed since Alexander Fleming discovered the antimicrobial activity of lysozyme, the first natural antibiotic isolated from our body. Since then, various types of molecules with antibiotic activity have been isolated from animals, insects, plants and bacteria, and their use has revolutionised clinical medicine. So far, more than 1200 types of peptides with antimicrobial activity have been isolated from various cells and tissues, and it appears all living organisms employ these antimicrobial peptides (AMPs) in their host defense. In the last decade, innate AMPs produced by mammals have been shown to be essential for the protection of skin and other organs. Their importance is due to their pleiotrophic functions to not only kill microbes but also control host physiological functions such as inflammation, angiogenesis and wound healing. Recent advances in our understanding of the function of AMPs have associated their altered production with various human diseases such as psoriasis, atopic dermatitis and rosacea. In this review, we summarize the history of AMP biology and provide an overview of recent research progress in this field.
doi:10.1038/jid.2011.387
PMCID: PMC3279605  PMID: 22158560
20.  Dermal adipocytes protect against invasive Staphylococcus aureus skin infection 
Science (New York, N.Y.)  2015;347(6217):67-71.
Adipocytes have been suggested to be immunologically active, but their role in host defense is unclear. We observed rapid proliferation of preadipocytes and expansion of the dermal fat layer after infection of the skin by Staphylococcus aureus. Impaired adipogenesis resulted in increased infection as seen in Zfp423nur12 mice or in mice given inhibitors of peroxisome proliferator–activated receptor γ. This host defense function was mediated through the production of cathelicidin antimicrobial peptide from adipocytes because cathelicidin expression was decreased by inhibition of adipogenesis, and adipocytes from Camp−/− mice lost the capacity to inhibit bacterial growth. Together, these findings show that the production of an antimicrobial peptide by adipocytes is an important element for protection against S. aureus infection of the skin.
doi:10.1126/science.1260972
PMCID: PMC4318537  PMID: 25554785
21.  Microbial Symbiosis with the Innate Immune Defense System of the Skin 
Skin protects itself against infection through a variety of mechanisms. Antimicrobial peptides (AMPs) are major contributors to cutaneous innate immunity, and this system, combined with the unique ionic, lipid and physical barrier of the epidermis is the first line defense against invading pathogens. However, recent studies have revealed that our skin’s innate immune system is not solely of human origin. Staphylococcus epidermidis, a major constituent of the normal microflora on healthy human skin, acts as a barrier against colonization of potentially pathogenic microbes and against overgrowth of already present opportunistic pathogens. Our resident commensal microbes produce their own AMPs, act to enhance the normal production of AMPs by keratinocytes, and are beneficial to maintaining inflammatory homeostasis by suppressing excess cytokine release after minor epidermal injury. These observations indicate that the normal human skin microflora protects skin via various modes of action, a conclusion supported by many lines of evidence associating diseases such as acne, atopic dermatitis, psoriasis and rosacea with an imbalance of the microflora even in the absence of classical infection. This review highlights recent observations on the importance of innate immune systems and the relationship with the normal skin microflora to maintain healthy skin.
doi:10.1038/jid.2011.182
PMCID: PMC3174284  PMID: 21697881
22.  Staphylococcus epidermidis in the human skin microbiome mediates fermentation to inhibit the growth of Propionibacterium acnes: Implications of probiotics in acne vulgaris 
Increasing evidence demonstrates that commensal microorganisms in the human skin microbiome help fight pathogens and maintain homeostasis of the microbiome. However, it is unclear how these microorganisms maintain biological balance when one of them overgrows. The overgrowth of Propionibacterium acnes (P. acnes), a commensal skin bacterium, has been associated with the progression of acne vulgaris. Our results demonstrate that skin microorganisms can mediate fermentation of glycerol, which is naturally produced in skin, to enhance their inhibitory effects on P. acnes growth. The skin microorganisms, most of which have been identified as Staphylococcus epidermidis (S. epidermidis), in the microbiome of human fingerprints can ferment glycerol and create inhibition zones to repel a colony of overgrown P. acnes. Succinic acid, one of four short-chain fatty acids (SCFAs) detected in fermented media by nuclear magnetic resonance (NMR) analysis, effectively inhibits the growth of P. acnes in vitro and in vivo. Both intralesional injection and topical application of succinic acid to P. acnes-induced lesions markedly suppress the P. acnes-induced inflammation in mice. We demonstrate for the first time that bacterial members in the skin microbiome can undergo fermentation to rein in the overgrowth of P. acnes. The concept of bacterial interference between P. acnes and S. epidermidis via fermentation can be applied to develop probiotics against acne vulgaris and other skin diseases. In addition, it will open up an entirely new area of study for the biological function of the skin microbiome in promoting human health.
doi:10.1007/s00253-013-5394-8
PMCID: PMC3888247  PMID: 24265031
Acne; Fermentation; P. acnes; Probiotic; S. epidermidis; Skin Microbiome
23.  Innate Immune Sensors Stimulate Inflammatory and Immunosuppressive Responses to UVB Radiation 
Almost 40 years from when it was first reported that UVB radiation exposure would modulate immune signaling, the photoimmunology field is still trying to understand the mechanisms by which UVB initiates inflammatory responses and modulates immune recognition. This commentary focuses on the ability of Toll-like receptors (TLRs), specifically TLR4 (Ahmad et al., 2014) and ligands such as damage-associated molecular patterns (DAMPs) released from injured cells to stimulate innate immune signaling and inflammatory cytokine production following UVB irradiation.
doi:10.1038/jid.2014.32
PMCID: PMC4271625  PMID: 24825061
24.  Cyclooxygenase-2 Enhances Antimicrobial Peptide Expression and Killing of Staphylococcus aureus 
Antimicrobial peptides such as human β-defensins (hBDs) and cathelicidins are critical for protection against infection and can be induced by activation of TLRs, a pathway that also activates cyclooxygenase(Cox)-2 expression. We hypothesized that Cox-2 is induced by TLR activation and is necessary for optimal AMP production, and that inhibitors of Cox-2 may therefore inhibit antimicrobial action. Normal human keratinocytes (NHEKs) stimulated with a TLR2/6 ligand, macrophage-activating lipo-peptide-2, or a TLR3 ligand, polyinosinic-polycytidylic acid, increased Cox-2 mRNA and protein and increased PGE2, a product of Cox-2. Treatment with a Cox-2 selective inhibitor (SC-58125) or Cox-2 small interfering RNA attenuated hBD2 and hBD3 production in NHEKs when stimulated with macrophage-activating lipopeptide-2, polyinosinic-polycytidylic acid, or UVB (15 mJ/cm2), but it did not attenuate vitamin D3-induced cathelicidin. SC-58125 also inhibited TLR-dependent NF-κB activation. Conversely, treatment with Cox-derived prostanoids PGD2 or 15-deoxy-Δ12,14-PGJ2 induced hBD3 or hBD2 and hBD3, respectively. The functional significance of these observations was seen in NHEKs that showed reduced anti-staphylococcal activity when treated with a Cox-2 inhibitor. These findings demonstrate a critical role for Cox-2 in hBD production and suggest that the use of Cox-2 inhibitors may adversely influence the risk for bacterial infection.
doi:10.4049/jimmunol.1002009
PMCID: PMC3025174  PMID: 20971925
25.  Cathelicidin-Deficient (Cnlp−/−) Mice Show Increased Susceptibility to Pseudomonas aeruginosa Keratitis 
Purpose
To examine the clinical progression and innate immune responses during Pseudomonas aeruginosa (PA) keratitis in cathelicidin-deficient (KO) mice.
Methods
PA (ATCC 19660) keratitis was induced in KO mice and wild-type (WT) littermates generated on a 129/SVJ background. Clinical score and histopathology were used to monitor the progression of infection at postinfection (PI) days 1, 3, 7, 14, and 21. Mouse corneas were harvested for viable bacteria quantitation, and myeloperoxidase (MPO) assays were performed to determine the number of infiltrating neutrophils. ELISA was used to quantitate interleukin (IL)-1β, IL-6, macrophage inflammatory peptide (MIP)-2, keratinocyte-derived chemokine (KC), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF) levels in the corneas.
Results
WT mice were resistant (cornea healed), whereas KO mice showed increased susceptibility (corneas failed to recover by 21 days or perforated) to PA infection. Clinical scores were significantly elevated in the infected corneas of KO mice versus WT mice at 7, 14, and 21 days PI. Absence of cathelicidin resulted in significantly delayed clearance of PA in the cornea and an increased number of infiltrating neutrophils at 1, 3, 7, and 14 days PI. KO mice also exhibited differential expression of protein levels for IL-1β, IL-6, MIP-2, KC, TNF-α, and VEGF up to day 21 PI compared with the WT mice.
Conclusions
Cathelicidin-deficient mice showed considerable susceptibility to PA keratitis. The present study demonstrates direct in vivo evidence that endogenous expression of cathelicidin provides defense against corneal PA infection indicating its importance in host innate immunity at the ocular surface.
doi:10.1167/iovs.07-0274
PMCID: PMC4234056  PMID: 17898271

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