DOI: 10.1111/exd.12401
Viewpoint
www.wileyonlinelibrary.com/journal/EXD
Face-to-face with anti-inflammatory therapy for rosacea € rgen Schauber Suzanna Salzer, Thomas Ruzicka and Ju Department of Dermatology and Allergy, Ludwig-Maximilian-University, Munich, Germany Correspondence: J€ urgen Schauber, MD, Department of Dermatology und Allergy, Ludwig-Maximilian-University, Frauenlobstr. 9-11, 80337 Munich, Germany, Tel.: +49-89-5160-6388, Fax: +49-89-5160-6389, e-mail: [email protected] Abstract: In the past, our understanding of rosacea has been inadequate and limited to descriptions of factors that exacerbate and improve the disease. While the pathophysiology of rosacea is complex and multifactorial, cathelicidin peptides have emerged as key players in the pathogenesis of this common dermatological disorder. This article correlates recent findings in abnormal cathelicidin production and proteolytic processing in rosacea with
therapeutic actions of current treatment options and, in this way, highlights potential points of intervention for the development of efficient therapeutic alternatives.
Introduction
cutaneous production of AMPs (7,12). Cathelicidin is one of the most well-characterized AMPs, and immunomodulatory properties unrelated to direct pathogen inactivation suggest a broader role in host defenses (7,13,14). Cathelicidin has been shown to contribute to the pathogenesis of rosacea and has additionally been implicated in the pathogenesis of various autoimmune and inflammatory diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis and atherosclerosis (15–17). Cathelicidin activity is regulated by proteolytic processing of the proform hCAP18 to a mature peptide (18). The expression and processing of the cathelicidin precursor protein, meanwhile, are largely dependent on the cellular and tissue microenvironment and are therefore rather specific for the disease state (14–16). In the facial skin of patients with rosacea, not only is the expression of cathelicidin elevated, but the proteolytically processed forms are different from those found in healthy individuals (10). Those found on normal facial skin function mainly as antibiotics with little influence on inflammation (19). On the other hand, LL-37, the predominant cathelicidin peptide in rosacea, has been shown to promote leucocyte chemotaxis and angiogenesis and is a significant contributor to the regulation of inflammation (9,10,20). In the skin, proteolytic activation of hCAP18 to LL-37 is accomplished by serine protease kallikrein 5 (KLK5), also known as stratum corneum tryptic enzyme (18). Increased expression of KLK5 was detected in rosacea skin, and injection of KLK5 into mouse skin induces inflammation by promoting cathelicidin processing (10). KLK5 is activated by matrix metalloproteinases (MMPs), which have been reported to be inhibited by doxycycline (13). Given that doxycycline is used in the systemic treatment for rosacea, Kanada et al. (13) investigated whether doxycycline inhibits the activation of cathelicidin. By inhibiting MMP activity, doxycycline does in fact indirectly inhibit serine protease activity, thereby preventing cathelicidin activation (13). This newly elucidated mechanism of action accounts for the efficacy of subantimicrobial doses (40 mg/day) of doxycycline, which has become the mainstay of systemic treatment for moderate-to-severe rosacea (13,21). Importantly, the likelihood of bacterial resistance and adverse side effects is decreased with low-dose doxycycline therapy
Rosacea is often described as a common, chronic cutaneous disorder that predominately affects the central face (1). This rather simple description is, however, complicated by a heterogeneous clinical picture characterized by transient flushing, persistent facial redness, telangiectases, and inflammatory papules and pustules. Ocular changes and hypertrophy of the sebaceous glands, with subsequent fibrosis, may also be present (2,3). Factors that exacerbate the disease, such as emotional stress, spicy foods, high temperatures, alcohol and sun exposure, are well defined, but a specific cause for rosacea has yet to be identified (4). While the diversity in clinical expression is most likely accompanied by diversity in aetiopathogenesis, recent studies suggest that dysfunction of the innate immune system may play an important role in the development of vascular abnormalities and inflammatory disease in patients with rosacea (5,6). More specifically, abnormal production and processing of cathelicidin antimicrobial peptides (AMPs), effector molecules of the innate immune system that have antimicrobial as well as immunomodulatory properties, has been implicated in the pathogenesis of rosacea (7,8). Cathelicidin peptide LL-37 and its fragments are vasoactive and proinflammatory, and increased levels are detectable in the skin of patients with rosacea (9–11). Aberrations in cathelicidin processing and an altered innate immune response account for many of the pathological changes typical of rosacea and are therefore reasonable targets for therapeutic intervention. While various treatment options are currently available, their use thus far has largely been empiric and the mechanisms mediating their therapeutic effects have been poorly understood (1,4). The rationale behind the efficacy of current therapeutic approaches becomes clearer, however, when considering rosacea as an innate immune-mediated disease. By focusing on the immunomodulatory effects of existing treatments, this article highlights potential points of intervention for the development of therapeutic alternatives.
Targeting excessive innate immune activation The skin is both a physical and immune antimicrobial barrier. The latter function is accomplished to a large extent by the
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 379–381
Key words: cathelicidin – doxycycline – innate immunity – protease activity – rosacea
Accepted for publication 27 March 2014
379
Salzer et al.
as compared with conventional (100–200 mg/day) antimicrobial therapy. Antibiotic stewardship, nevertheless, favours the development of non-antibiotic alternatives, and cathelicidin processing has been shown to be an appropriate target for prospective rosacea therapy (Fig. 1). Insight into the anti-inflammatory effects of doxycycline prompted interest in the mechanism of action of azelaic acid (AzA), a gel commonly used in rosacea therapy. AzA has previously been shown to ameliorate the neutrophilic production of reactive oxygen species (ROS), which are believed to play a significant role in the pathophysiology of rosacea (22). ROS, such as superoxide, hydrogen peroxide and hydroxyl radicals, are capable of initiating oxidative reactions and, in this manner, promote oxidative tissue damage and subsequent inflammation. Being that the skin is constantly exposed to oxygen and ultraviolet radiation, two factors that are vital to ROS generation, it is particularly susceptible to oxidative tissue damage (22–24). Interestingly, this susceptibility may be enhanced by the presence of LL-37, which has recently been implicated in the production of ROS (22,25). Neutrophils, effector cells in innate immunity, are responsible for ROS production, and LL-37 has been reported to suppress the apoptosis of neutrophils, in addition to inducing their migration (22,25). Furthermore, Zheng et al. (25) have demonstrated that LL-37 stimulates the generation of ROS in a time- and dose-dependent manner, most likely through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and intra-cellular Ca+2 mobilization. The importance of ROS in rosacea pathophysiology is underscored by the effectiveness of metronidazole, the most commonly used topical agent in the treatment for rosacea (23,26). Its clinical efficacy has been attributed to its ability to decrease ROS generation and inactivate existing ROS production (23). While further research is necessary to elucidate a clearer picture of the mechanism of action of metronidazole and determine whether it influences cathelicidin expression or proteolytic activation, current research into AzA activity has uncovered that AzA additionally plays a role in mediating cathelicidin processing. Treatment with AzA inhibited KLK5 in keratinocytes in vitro and the gene
Isotretinoin
Metronidazole
Doxycycline Azelaic acid
UV light, heat etc.
TLR2
ROS formation
MMPs
Vascular Dysregulation Chemotaxis
Serine proteases e.g. kallikrein 5 hCAP18
LL-37 peptide + fragments
Inflammation Erythema
Direct LL-37 inhibitors
Figure 1. Increased cathelicidin production and processing to active forms such as LL-37 accounts for many of the symptoms observed in rosacea. Effective available therapies for rosacea such as isotretinoin, doxycycline, azelaic acid and metronidazole mediate their effects through blocking distinct steps in the pathophysiology of the disease and highlight points of potential intervention. Similarly, emerging therapeutic alternatives such as LL-37 blockers may effectively target the aberrant activation of the innate immune system that is characteristic of individuals with rosacea.
380
expression of KLK5 and cathelicidin in mouse skin in vivo (4). The ability of AzA to inhibit KLK5 was further evaluated in patients with rosacea, where treatment with AzA 15% gel twice daily for 16 weeks resulted in a reduction in cathelicidin and KLK5 messenger RNA (4). The utility of AzA in the treatment for rosacea seems to be additionally related to its ability to counter the abnormally high protease activity that is characteristic of this disease. AzA activity confirms that serine protease inhibitors have a therapeutic effect in rosacea (Fig. 1). While the efficacy of established therapies such as doxycycline and AzA largely focuses on the proteolytic activation of hCAP18, and thereby the production of LL-37, the LL-37 peptide itself is emerging as a potential therapeutic target. Semisynthetic glycosaminoglycan esthers (SAGEs), a family of sulphated and metabolically stabilized anionic polysaccharide derivates, have been shown to inhibit the inflammatory activity of cathelicidins by directly binding to LL-37 (5). Injection of LL-37 into the skin of mice leads to rosacea-like skin changes dominated by inflammation and vascular dilation (5,10). Concomitant injection of SAGE GM-111, however, significantly reduced LL-37-induced inflammation (5). Furthermore, topical application of GM-111 following intra-dermal injection of LL-37 diminished the resultant erythema and polymorphonuclear granulocyte infiltration. Successful experimentation with topically applied SAGE GM-111 exposes the LL-37 peptide as a promising target for topical rosacea treatment.
Curbing innate sensors to decrease the inflammatory response The innate immune defenses of the skin are charged with the responsibility of protecting against pathogens and environmental insults. The aberrant innate immune responses that characterize individuals with rosacea coincide with an abnormal sensitivity to external stimuli. External triggers such as ultraviolet light and heat, for example, are known to aggravate the inflammation and vascular dilation associated with the disease. Enhanced immune detection and response is attributable in part to increased expression of toll-like receptor 2 (TLR2) in patients with rosacea (27). Toll-like receptors are important immune sensors that detect pathogen- or danger-associated patterns. In keratinocytes, activation of TLR2 promotes skin protease activity by increasing KLK5 expression (27). Increased TLR2 expression therefore may be the link between external insults and cathelicidin-mediated abnormalities – and a possible target for novel therapies (3). While isotretinoin has long been recognized to be valuable for the systemic treatment for severe forms of rosacea, its use continues to be off-label due to insufficient evidence-based clinical studies (28,29). In 2009, nonetheless, a randomized, double-blind, non-inferiority trial compared the use of oral isotretinoin with both doxycycline and placebo and found isotretinoin 0.3 mg/kg to be well suited for the treatment for severe and moderate rosacea forms (29). Intra-cellularly, 13-cis-retinoic acid, isotretinoin, is metabolized into other isomers, such as all-trans retinoic acid and 9-cis-retinoic acid. Both retinoic acid isomers induce KLK5 and KLK7 expression and protease activity in cultured keratinocytes (30). This increase in protease activity, however, does not parallel an increase in cathelicidin processing. Nevertheless, in the light of these data, the anti-inflammatory effect of retinoids in rosacea might not be mediated by direct effects on the kallikrein/cathelicidin system. Given that all-trans retinoic acid has been reported to
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 379–381
Anti-inflammatory therapy for rosacea
down-regulate TLR2 expression and function in human monocytes in vitro and in clinical studies in vivo, the effectiveness of systemic isotretinoin in the treatment for rosacea rather supports the role of TLR2 in rosacea pathogenesis (31, 32). An expansive side effect profile and teratogenicity concerns, however, limit the use of isotretinoin, and the potential of TLR2 as a therapeutic target in rosacea warrants further investigation (Fig. 1).
Conclusion and outlook Affecting approximately 5–10% of the general population, rosacea is a chronic and oftentimes disfiguring disease that demands lifelong treatment and attention (2,3). In the past, inadequate understanding of the pathological process responsible for rosacea has stymied efforts to develop innovative treatment options. Recent insight into the pathogenesis of the disease, however, has renewed interest in extending the therapeutic armamentarium against rosacea. Current studies expose the rationale behind the use of existing therapies, namely low-dose doxycycline, AzA and isotretinoin, and thereby confer a promising outlook on the development of prospective novel therapeutic options that deliberately target the molecular pathogenesis of the disease. Emerging therapeutic alternatives may effectively target the aberrant activation of the innate immune system that is characteristic of individuals with rosacea, and curb the proteolytic activation and processing of the cathelicidin peptide (Fig. 1). Recently, novel 1,2,4-triazole derivatives that
transiently inactivate human kallikreins, including KLK5, and non-covalent inhibitors of KLK5 have been identified (33,34). Further experimentation is of interest to explore the potential of using such compounds to target increased kallikrein activity in rosacea treatment. The advent of innovative therapeutic targets for rosacea treatment underscores the need for clinical studies that would allow for the comparison of emerging therapies and for the determination of optimal treatment duration. The scarcity of clinical trials regarding rosacea therapy thus far is partly attributable to the fact that rosacea is a clinical diagnosis, where laboratory tests for monitoring clinical progression are lacking (35). Given recent evidence suggests that serine protease activity may shadow disease activity in rosacea, it may be worthwhile to consider serine protease activity as a candidate for evaluating disease activity (4,10). Furthermore, serine protease activity may potentially identify patients at risk of disease exacerbation and allow of early intervention. Recent advancements in rosacea research therefore encourage a very optimistic view of prospective rosacea management.
Acknowledgements SS, TR and JS wrote the manuscript. JS’s research is funded by the Deutsche Forschungsgemeinschaft and the Else Kroener Fresenius Stiftung.
Conflict of interest The authors declare no conflict of interest.
References
1 Elewski B E, Draelos Z, Dr eno B et al. J Eur Acad Dermatol Venereol 2011: 25: 88. 2 Powell F C. N Engl J Med 2005: 352: 793. 3 Crawford G H, Pelle M T, James W D. J Am Acad Dermatol 2004: 51: 327. 4 Coda A B, Hatta T, Miller J et al. J Am Acad Dermatol 2013: 69: 570–577. 5 Zhang J, Xu X, Rao N V et al. PLoS ONE 2011: 6: e16658. 6 Yamasaki K, Gallo R L. J Dermatol Sci 2009: 55: 77. 7 Schauber J, Gallo R L. J Allergy Clin Immunol 2008: 122: 261. 8 Zanetti M. J Leukoc Biol 2004: 75: 39. 9 Koczulla R, von Degenfeld G, Kupatt C et al. J Clin Invest 2003: 111: 1665. 10 Yamasaki K, Di Nardo A, Bardan A et al. Nat Med 2007: 13: 975. 11 Casas C, Paul C, Lahfa M et al. Exp Dermatol 2012: 21: 906–910. 12 Borkowski A W, Gallo R L. J Invest Dermatol 2011: 131: 285. 13 Kanada K N, Nakatsuji T, Gallo R L. J Invest Dermatol 2012: 132: 1435–1442.
14 Nijnik A, Hancock R E. Curr Opin Hematol 2009: 16: 41–47. 15 Morizane S, Gallo R L. J Dermatol 2012: 39: 225–230. 16 Kahlenberg J M, Kaplan M J. J Immunol 2013: 191: 4895–4901. 17 Reinholz M, Ruzicka T, Schauber J. Ann Dermatol 2012: 24: 126–135. 18 Yamasaki K, Schauber J, Coda A et al. FASEB J 2006: 20: 2068. 19 Yamasaki K, Gallo R L. J Investig Dermatol Symp Proc 2011: 15: 12–15. 20 Ramos R, Silva J P, Rodrigues A C et al. Peptides 2011: 31: 1469. 21 Reinholz M, Tietze J K, Kilian K et al. J Dtsch Dermatol Ges 2013: 11: 768–780; 768–79. 22 Jones D A. J Clin Aesthet Dermatol 2009: 2: 26–30. €nerbein A, Getie M et al. J 23 Narayanan S, Hu Pharm Pharmacol 2007: 59: 1125–1130. 24 Briganti S, Flori E, Mastrofrancesco A et al. Exp Dermatol 2013: 22: 41–47. 25 Zheng Y, Niyonsaba F, Ushio H et al. Br J Dermatol 2007: 157: 1124–1131.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 379–381
26 Korting H C. J Eur Acad Dermatol Venereol 2009: 23: 876–882. 27 Yamasaki K, Kanada K, Macleod D T et al. J Invest Dermatol 2011: 131: 688–697. 28 Fallen R S, Gooderham M. Skin Therapy Lett 2012: 17: 1–4. E L et al. J 29 Gollnick H, Blume-Peytavi U, Szabo Dtsch Dermatol Ges 2010: 8: 505–515. 30 Morizane S, Yamasaki K, Kabigting F D et al. J Invest Dermatol 2010: 130: 1297–1306. 31 Liu P T, Krutzik S R, Kim J et al. J Immunol 2005: 174: 2467–2470. 32 Dispenza M C, Wolpert E B, Gilliland K L et al. J Invest Dermatol 2012: 132: 2198– 2205. 33 Tan X, Furio L, Reboud-Ravaux M et al. Bioorg Med Chem Lett 2013: 23: 4547–4551. 34 Tan X, Bertonati C, Qin L et al. Eur J Med Chem 2013: 70: 661–668. 35 Gessert C E, Bamford J T. Int J Dermatol 2003: 42: 444–448.
381
Viewpoint
www.wileyonlinelibrary.com/journal/EXD
Face-to-face with anti-inflammatory therapy for rosacea € rgen Schauber Suzanna Salzer, Thomas Ruzicka and Ju Department of Dermatology and Allergy, Ludwig-Maximilian-University, Munich, Germany Correspondence: J€ urgen Schauber, MD, Department of Dermatology und Allergy, Ludwig-Maximilian-University, Frauenlobstr. 9-11, 80337 Munich, Germany, Tel.: +49-89-5160-6388, Fax: +49-89-5160-6389, e-mail: [email protected] Abstract: In the past, our understanding of rosacea has been inadequate and limited to descriptions of factors that exacerbate and improve the disease. While the pathophysiology of rosacea is complex and multifactorial, cathelicidin peptides have emerged as key players in the pathogenesis of this common dermatological disorder. This article correlates recent findings in abnormal cathelicidin production and proteolytic processing in rosacea with
therapeutic actions of current treatment options and, in this way, highlights potential points of intervention for the development of efficient therapeutic alternatives.
Introduction
cutaneous production of AMPs (7,12). Cathelicidin is one of the most well-characterized AMPs, and immunomodulatory properties unrelated to direct pathogen inactivation suggest a broader role in host defenses (7,13,14). Cathelicidin has been shown to contribute to the pathogenesis of rosacea and has additionally been implicated in the pathogenesis of various autoimmune and inflammatory diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis and atherosclerosis (15–17). Cathelicidin activity is regulated by proteolytic processing of the proform hCAP18 to a mature peptide (18). The expression and processing of the cathelicidin precursor protein, meanwhile, are largely dependent on the cellular and tissue microenvironment and are therefore rather specific for the disease state (14–16). In the facial skin of patients with rosacea, not only is the expression of cathelicidin elevated, but the proteolytically processed forms are different from those found in healthy individuals (10). Those found on normal facial skin function mainly as antibiotics with little influence on inflammation (19). On the other hand, LL-37, the predominant cathelicidin peptide in rosacea, has been shown to promote leucocyte chemotaxis and angiogenesis and is a significant contributor to the regulation of inflammation (9,10,20). In the skin, proteolytic activation of hCAP18 to LL-37 is accomplished by serine protease kallikrein 5 (KLK5), also known as stratum corneum tryptic enzyme (18). Increased expression of KLK5 was detected in rosacea skin, and injection of KLK5 into mouse skin induces inflammation by promoting cathelicidin processing (10). KLK5 is activated by matrix metalloproteinases (MMPs), which have been reported to be inhibited by doxycycline (13). Given that doxycycline is used in the systemic treatment for rosacea, Kanada et al. (13) investigated whether doxycycline inhibits the activation of cathelicidin. By inhibiting MMP activity, doxycycline does in fact indirectly inhibit serine protease activity, thereby preventing cathelicidin activation (13). This newly elucidated mechanism of action accounts for the efficacy of subantimicrobial doses (40 mg/day) of doxycycline, which has become the mainstay of systemic treatment for moderate-to-severe rosacea (13,21). Importantly, the likelihood of bacterial resistance and adverse side effects is decreased with low-dose doxycycline therapy
Rosacea is often described as a common, chronic cutaneous disorder that predominately affects the central face (1). This rather simple description is, however, complicated by a heterogeneous clinical picture characterized by transient flushing, persistent facial redness, telangiectases, and inflammatory papules and pustules. Ocular changes and hypertrophy of the sebaceous glands, with subsequent fibrosis, may also be present (2,3). Factors that exacerbate the disease, such as emotional stress, spicy foods, high temperatures, alcohol and sun exposure, are well defined, but a specific cause for rosacea has yet to be identified (4). While the diversity in clinical expression is most likely accompanied by diversity in aetiopathogenesis, recent studies suggest that dysfunction of the innate immune system may play an important role in the development of vascular abnormalities and inflammatory disease in patients with rosacea (5,6). More specifically, abnormal production and processing of cathelicidin antimicrobial peptides (AMPs), effector molecules of the innate immune system that have antimicrobial as well as immunomodulatory properties, has been implicated in the pathogenesis of rosacea (7,8). Cathelicidin peptide LL-37 and its fragments are vasoactive and proinflammatory, and increased levels are detectable in the skin of patients with rosacea (9–11). Aberrations in cathelicidin processing and an altered innate immune response account for many of the pathological changes typical of rosacea and are therefore reasonable targets for therapeutic intervention. While various treatment options are currently available, their use thus far has largely been empiric and the mechanisms mediating their therapeutic effects have been poorly understood (1,4). The rationale behind the efficacy of current therapeutic approaches becomes clearer, however, when considering rosacea as an innate immune-mediated disease. By focusing on the immunomodulatory effects of existing treatments, this article highlights potential points of intervention for the development of therapeutic alternatives.
Targeting excessive innate immune activation The skin is both a physical and immune antimicrobial barrier. The latter function is accomplished to a large extent by the
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 379–381
Key words: cathelicidin – doxycycline – innate immunity – protease activity – rosacea
Accepted for publication 27 March 2014
379
Salzer et al.
as compared with conventional (100–200 mg/day) antimicrobial therapy. Antibiotic stewardship, nevertheless, favours the development of non-antibiotic alternatives, and cathelicidin processing has been shown to be an appropriate target for prospective rosacea therapy (Fig. 1). Insight into the anti-inflammatory effects of doxycycline prompted interest in the mechanism of action of azelaic acid (AzA), a gel commonly used in rosacea therapy. AzA has previously been shown to ameliorate the neutrophilic production of reactive oxygen species (ROS), which are believed to play a significant role in the pathophysiology of rosacea (22). ROS, such as superoxide, hydrogen peroxide and hydroxyl radicals, are capable of initiating oxidative reactions and, in this manner, promote oxidative tissue damage and subsequent inflammation. Being that the skin is constantly exposed to oxygen and ultraviolet radiation, two factors that are vital to ROS generation, it is particularly susceptible to oxidative tissue damage (22–24). Interestingly, this susceptibility may be enhanced by the presence of LL-37, which has recently been implicated in the production of ROS (22,25). Neutrophils, effector cells in innate immunity, are responsible for ROS production, and LL-37 has been reported to suppress the apoptosis of neutrophils, in addition to inducing their migration (22,25). Furthermore, Zheng et al. (25) have demonstrated that LL-37 stimulates the generation of ROS in a time- and dose-dependent manner, most likely through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and intra-cellular Ca+2 mobilization. The importance of ROS in rosacea pathophysiology is underscored by the effectiveness of metronidazole, the most commonly used topical agent in the treatment for rosacea (23,26). Its clinical efficacy has been attributed to its ability to decrease ROS generation and inactivate existing ROS production (23). While further research is necessary to elucidate a clearer picture of the mechanism of action of metronidazole and determine whether it influences cathelicidin expression or proteolytic activation, current research into AzA activity has uncovered that AzA additionally plays a role in mediating cathelicidin processing. Treatment with AzA inhibited KLK5 in keratinocytes in vitro and the gene
Isotretinoin
Metronidazole
Doxycycline Azelaic acid
UV light, heat etc.
TLR2
ROS formation
MMPs
Vascular Dysregulation Chemotaxis
Serine proteases e.g. kallikrein 5 hCAP18
LL-37 peptide + fragments
Inflammation Erythema
Direct LL-37 inhibitors
Figure 1. Increased cathelicidin production and processing to active forms such as LL-37 accounts for many of the symptoms observed in rosacea. Effective available therapies for rosacea such as isotretinoin, doxycycline, azelaic acid and metronidazole mediate their effects through blocking distinct steps in the pathophysiology of the disease and highlight points of potential intervention. Similarly, emerging therapeutic alternatives such as LL-37 blockers may effectively target the aberrant activation of the innate immune system that is characteristic of individuals with rosacea.
380
expression of KLK5 and cathelicidin in mouse skin in vivo (4). The ability of AzA to inhibit KLK5 was further evaluated in patients with rosacea, where treatment with AzA 15% gel twice daily for 16 weeks resulted in a reduction in cathelicidin and KLK5 messenger RNA (4). The utility of AzA in the treatment for rosacea seems to be additionally related to its ability to counter the abnormally high protease activity that is characteristic of this disease. AzA activity confirms that serine protease inhibitors have a therapeutic effect in rosacea (Fig. 1). While the efficacy of established therapies such as doxycycline and AzA largely focuses on the proteolytic activation of hCAP18, and thereby the production of LL-37, the LL-37 peptide itself is emerging as a potential therapeutic target. Semisynthetic glycosaminoglycan esthers (SAGEs), a family of sulphated and metabolically stabilized anionic polysaccharide derivates, have been shown to inhibit the inflammatory activity of cathelicidins by directly binding to LL-37 (5). Injection of LL-37 into the skin of mice leads to rosacea-like skin changes dominated by inflammation and vascular dilation (5,10). Concomitant injection of SAGE GM-111, however, significantly reduced LL-37-induced inflammation (5). Furthermore, topical application of GM-111 following intra-dermal injection of LL-37 diminished the resultant erythema and polymorphonuclear granulocyte infiltration. Successful experimentation with topically applied SAGE GM-111 exposes the LL-37 peptide as a promising target for topical rosacea treatment.
Curbing innate sensors to decrease the inflammatory response The innate immune defenses of the skin are charged with the responsibility of protecting against pathogens and environmental insults. The aberrant innate immune responses that characterize individuals with rosacea coincide with an abnormal sensitivity to external stimuli. External triggers such as ultraviolet light and heat, for example, are known to aggravate the inflammation and vascular dilation associated with the disease. Enhanced immune detection and response is attributable in part to increased expression of toll-like receptor 2 (TLR2) in patients with rosacea (27). Toll-like receptors are important immune sensors that detect pathogen- or danger-associated patterns. In keratinocytes, activation of TLR2 promotes skin protease activity by increasing KLK5 expression (27). Increased TLR2 expression therefore may be the link between external insults and cathelicidin-mediated abnormalities – and a possible target for novel therapies (3). While isotretinoin has long been recognized to be valuable for the systemic treatment for severe forms of rosacea, its use continues to be off-label due to insufficient evidence-based clinical studies (28,29). In 2009, nonetheless, a randomized, double-blind, non-inferiority trial compared the use of oral isotretinoin with both doxycycline and placebo and found isotretinoin 0.3 mg/kg to be well suited for the treatment for severe and moderate rosacea forms (29). Intra-cellularly, 13-cis-retinoic acid, isotretinoin, is metabolized into other isomers, such as all-trans retinoic acid and 9-cis-retinoic acid. Both retinoic acid isomers induce KLK5 and KLK7 expression and protease activity in cultured keratinocytes (30). This increase in protease activity, however, does not parallel an increase in cathelicidin processing. Nevertheless, in the light of these data, the anti-inflammatory effect of retinoids in rosacea might not be mediated by direct effects on the kallikrein/cathelicidin system. Given that all-trans retinoic acid has been reported to
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 379–381
Anti-inflammatory therapy for rosacea
down-regulate TLR2 expression and function in human monocytes in vitro and in clinical studies in vivo, the effectiveness of systemic isotretinoin in the treatment for rosacea rather supports the role of TLR2 in rosacea pathogenesis (31, 32). An expansive side effect profile and teratogenicity concerns, however, limit the use of isotretinoin, and the potential of TLR2 as a therapeutic target in rosacea warrants further investigation (Fig. 1).
Conclusion and outlook Affecting approximately 5–10% of the general population, rosacea is a chronic and oftentimes disfiguring disease that demands lifelong treatment and attention (2,3). In the past, inadequate understanding of the pathological process responsible for rosacea has stymied efforts to develop innovative treatment options. Recent insight into the pathogenesis of the disease, however, has renewed interest in extending the therapeutic armamentarium against rosacea. Current studies expose the rationale behind the use of existing therapies, namely low-dose doxycycline, AzA and isotretinoin, and thereby confer a promising outlook on the development of prospective novel therapeutic options that deliberately target the molecular pathogenesis of the disease. Emerging therapeutic alternatives may effectively target the aberrant activation of the innate immune system that is characteristic of individuals with rosacea, and curb the proteolytic activation and processing of the cathelicidin peptide (Fig. 1). Recently, novel 1,2,4-triazole derivatives that
transiently inactivate human kallikreins, including KLK5, and non-covalent inhibitors of KLK5 have been identified (33,34). Further experimentation is of interest to explore the potential of using such compounds to target increased kallikrein activity in rosacea treatment. The advent of innovative therapeutic targets for rosacea treatment underscores the need for clinical studies that would allow for the comparison of emerging therapies and for the determination of optimal treatment duration. The scarcity of clinical trials regarding rosacea therapy thus far is partly attributable to the fact that rosacea is a clinical diagnosis, where laboratory tests for monitoring clinical progression are lacking (35). Given recent evidence suggests that serine protease activity may shadow disease activity in rosacea, it may be worthwhile to consider serine protease activity as a candidate for evaluating disease activity (4,10). Furthermore, serine protease activity may potentially identify patients at risk of disease exacerbation and allow of early intervention. Recent advancements in rosacea research therefore encourage a very optimistic view of prospective rosacea management.
Acknowledgements SS, TR and JS wrote the manuscript. JS’s research is funded by the Deutsche Forschungsgemeinschaft and the Else Kroener Fresenius Stiftung.
Conflict of interest The authors declare no conflict of interest.
References
1 Elewski B E, Draelos Z, Dr eno B et al. J Eur Acad Dermatol Venereol 2011: 25: 88. 2 Powell F C. N Engl J Med 2005: 352: 793. 3 Crawford G H, Pelle M T, James W D. J Am Acad Dermatol 2004: 51: 327. 4 Coda A B, Hatta T, Miller J et al. J Am Acad Dermatol 2013: 69: 570–577. 5 Zhang J, Xu X, Rao N V et al. PLoS ONE 2011: 6: e16658. 6 Yamasaki K, Gallo R L. J Dermatol Sci 2009: 55: 77. 7 Schauber J, Gallo R L. J Allergy Clin Immunol 2008: 122: 261. 8 Zanetti M. J Leukoc Biol 2004: 75: 39. 9 Koczulla R, von Degenfeld G, Kupatt C et al. J Clin Invest 2003: 111: 1665. 10 Yamasaki K, Di Nardo A, Bardan A et al. Nat Med 2007: 13: 975. 11 Casas C, Paul C, Lahfa M et al. Exp Dermatol 2012: 21: 906–910. 12 Borkowski A W, Gallo R L. J Invest Dermatol 2011: 131: 285. 13 Kanada K N, Nakatsuji T, Gallo R L. J Invest Dermatol 2012: 132: 1435–1442.
14 Nijnik A, Hancock R E. Curr Opin Hematol 2009: 16: 41–47. 15 Morizane S, Gallo R L. J Dermatol 2012: 39: 225–230. 16 Kahlenberg J M, Kaplan M J. J Immunol 2013: 191: 4895–4901. 17 Reinholz M, Ruzicka T, Schauber J. Ann Dermatol 2012: 24: 126–135. 18 Yamasaki K, Schauber J, Coda A et al. FASEB J 2006: 20: 2068. 19 Yamasaki K, Gallo R L. J Investig Dermatol Symp Proc 2011: 15: 12–15. 20 Ramos R, Silva J P, Rodrigues A C et al. Peptides 2011: 31: 1469. 21 Reinholz M, Tietze J K, Kilian K et al. J Dtsch Dermatol Ges 2013: 11: 768–780; 768–79. 22 Jones D A. J Clin Aesthet Dermatol 2009: 2: 26–30. €nerbein A, Getie M et al. J 23 Narayanan S, Hu Pharm Pharmacol 2007: 59: 1125–1130. 24 Briganti S, Flori E, Mastrofrancesco A et al. Exp Dermatol 2013: 22: 41–47. 25 Zheng Y, Niyonsaba F, Ushio H et al. Br J Dermatol 2007: 157: 1124–1131.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 379–381
26 Korting H C. J Eur Acad Dermatol Venereol 2009: 23: 876–882. 27 Yamasaki K, Kanada K, Macleod D T et al. J Invest Dermatol 2011: 131: 688–697. 28 Fallen R S, Gooderham M. Skin Therapy Lett 2012: 17: 1–4. E L et al. J 29 Gollnick H, Blume-Peytavi U, Szabo Dtsch Dermatol Ges 2010: 8: 505–515. 30 Morizane S, Yamasaki K, Kabigting F D et al. J Invest Dermatol 2010: 130: 1297–1306. 31 Liu P T, Krutzik S R, Kim J et al. J Immunol 2005: 174: 2467–2470. 32 Dispenza M C, Wolpert E B, Gilliland K L et al. J Invest Dermatol 2012: 132: 2198– 2205. 33 Tan X, Furio L, Reboud-Ravaux M et al. Bioorg Med Chem Lett 2013: 23: 4547–4551. 34 Tan X, Bertonati C, Qin L et al. Eur J Med Chem 2013: 70: 661–668. 35 Gessert C E, Bamford J T. Int J Dermatol 2003: 42: 444–448.
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