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See related article on pg 2019 myelinase, secretory phospholipase A2, and neutral lipases, and proteases such as chemotryptic enzymes (kallikreins) Lamellar Bodies: The Key to and cathepsins, are present in LBs (Feingold, 2007). In addition, enzyme inhibitors, such as the serine protease Cutaneous Barrier Function inhibitor, elafin, are also packaged into Kenneth R. Feingold1,2 LBs. Moreover, antimicrobial peptides, such as human b-defensin 2 and the The two primary barrier functions of skin (permeability and microbial barriers) are cathelicidin LL-37, are also present in provided by lipids and proteins delivered to the extracellular spaces of the stratum LBs (Oren et al., 2003; Braff et al., corneum by the secretion of lamellar bodies. Owing to their importance in this 2005). Because of the central impor- process, the mechanisms of and the factors regulating lamellar body formation tance of LB in the development of a must be better understood. Tarutani et al. (2012) provide data furthering the competent permeability and antimicro- concept of the importance of the Golgi network in lamellar body formation and bial barrier, information on the mecha- the necessity of acidification of the Golgi for normal function. nisms of LB formation and the factors Journal of Investigative Dermatology (2012) 132, 1951–1953. doi:10.1038/jid.2012.177 that regulate the rate of formation are needed. Previous studies by our group have shown that the incorporation of the lipid constituents of LBs and the enzymes in It has been recognized for many years that epidermis (Elias and Choi, 2005). The LBs occur coordinately and in parallel the cutaneous permeability barrier is cutaneous permeability barrier is media- (Rassner et al., 1999). After acute perme- abnormal in patients with atopic dermatitis ted by extracellular lipids, cholesterol, ability barrier disruption, LBs are rapidly and psoriasis, but this was consi- free fatty acids, and ceramides, which secreted by the stratum granulosum cells dered a secondary defect owing to under- form extracellular lipid–enriched lamellar and new LBs quickly form (Rassner lying immunological abnormalities and/or membranes between the corneocytes et al., 1999; Feingold, 2007). The appear- inflammation. However, recent studies that block the movement of water and ance of lipids and enzymes in these new have demonstrated that genetic abnormal- electrolytes (Feingold, 2007). The anti- LB occurs simultaneously (Rassner et al., ities in filaggrin lead to defects in cuta- microbial barrier is mediated by both 1999). Inhibiting lipid synthesis prevents neous permeability barrier function and lipids, particularly free fatty acids, and the delivery of lipids to LBs and also predispose to the development of atopic antimicrobial peptides, such as the beta- prevents the incorporation of enzymes dermatitis (Irvine et al., 2011). These defensins and cathelicidins, which also into the LBs (Rassner et al., 1999). studies have rekindled interest in the are localized to the extracellular spaces Providing exogenous lipids restores the abnormal cutaneous barrier as a primary of the stratum corneum (Elias and Choi, delivery of lipids to LBs and also leads to defect (Irvine et al., 2011). In addition, 2005; Feingold, 2007). Of particular note, the incorporation of enzymes into LBs, genetic studies have also suggested that both the lipids that form the permeability indicating that lipids have a key role in the pathogenesis of psoriasis may similarly barrier and the antimicrobial peptides facilitating the incorporation of the involve abnormalities in cutaneous barrier are delivered to the extracellular spaces enzymes into LBs (Rassner et al., 1999). function (Capon et al., 2012). Thus, cuta- of the stratum corneum by the secretion The expression of antimicrobial pep- neous barrier function has left the back- of lamellar bodies (LBs; Elias and Choi, tides in the epidermis is also co-regulated waters of dermatology research to become 2005; Feingold, 2007). with permeability barrier function (Aberg an area of increasing interest and study. LBs are ovoid secretory organelles that et al., 2008). Disruption of the perme- Although the skin has many barrier are first observed in the upper stratum ability barrier stimulates antimicrobial properties, the two most important are spinosum layer of the epidermis, with peptide production (Aberg et al., 2008). creating a barrier against the movement increasing numbers found in the stratum Moreover, in CRAMP / mice, the of water and electrolytes (permeability granulosum layer (Feingold, 2007). LBs synthesis of LBs following acute barrier barrier), and creating a barrier against contain phospholipids, glucosylcera- disruption is abnormal, leading to abnor- the entry of microorganisms (antimicro- mides, sphingomyelin, and cholesterol malities in permeability barrier homeo- bial barrier) (Elias and Choi, 2005). Both (Feingold, 2007). In addition, numerous stasis (Aberg et al., 2008). The density of these barriers are localized primarily enzymes, including lipid hydrolases such of LBs in stratum granulosum cells is to the stratum corneum layer of the as b glucocerebrosidase, acidic sphingo- normal, but the internal lamellar cargo of the LBs is often sparse in CRAMP / mice (Aberg et al., 2008). This suggests 1 Metabolism Section, Medical Service and Dermatology Service, Veterans Affairs Medical Center, that CRAMP has an important role in the San Francisco, California, USA and 2Departments of Medicine and Dermatology, University of California, San Francisco, San Francisco, California, USA incorporation and/or organization of lipids Correspondence: Kenneth R. Feingold, Metabolism Section (111F), Veterans Affairs Medical Center, 4150 into LBs. Despite the paucity of lamellar / Clement Street, San Francisco, California 94121, USA. E-mail: [email protected] contents in CRAMP mice, other

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cient in GPHR, indicating an abnormal Clinical Implications permeability barrier. These observations Lamellar bodies have the central role in the formation of the provide further evidence indicating that permeability and antimicrobial barriers. LBs are derived from the Golgi appa- ratus, and that acidification of the Golgi Lamellar bodies are derived from the Golgi apparatus, and acidification is required for this process to proceed of the Golgi is required for this process to proceed normally. normally. Additional studies have suggested that the pathogenesis of psoriasis Although this study further advances and atopic dermatitis may include primary abnormalities in cutaneous our understanding of LB formation, many barrier function. questions remain. After acute barrier dis- ruption, there is a marked acceleration in LB formation. What are the signaling pathways that lead to this increase? Is the rate of LB formation linked with the rate proteins (e.g., the hydrolytic enzyme, acid member of the ATP-binding cassette super- of LB secretion, and if so, what signaling lipase) are packaged in LBs normally, family, facilitates the transport of choles- pathways link these processes? Although indicating that the incorporation of these terol across the plasma membrane to HDL ABCA12 is required for the transport of enzymes into LBs is not dependent on particles. Our laboratory has observed glucosylceramides into LBs, how are the CRAMP (Aberg et al., 2008). Interestingly, that ABCG1-null mice display abnormal other lipid constituents of LBs transported in this model, as compared with inhibiting LB contents and secretion, leading to into LBs? What are the pathways by lipid synthesis, the absence of lipid incor- impaired lamellar bilayer formation, sug- which enzymes and antimicrobial pep- poration into LBs does not prevent the gesting a potential role for ABCG1 in LB tides are incorporated into LBs? How is packaging of enzymes into LBs, suggest- formation (Jiang et al., 2010). the incorporation of these various compo- ing that the formation of LBs may be a Morphological observations have nents coordinated? Is the incorporation complex multistep process (Aberg et al., demonstrated that nascent LBs appear of the various components sequential 2008). Whether lipids also have a key role to bud off the cisternae of the trans-Golgi or simultaneous, and is the incorporation in facilitating the incorporation of anti- network, a process that accelerates after of certain components dependent on microbial peptides into LBs has not yet acute barrier disruption when LB forma- other components? Given the central role been determined. tion is accelerated (Elias et al., 1998). In of LBs in the formation of both the The pathways that mediate the entry of support of an important role of the Golgi, permeability and antimicrobial barrier, lipids into LBs have not been fully eluci- brefeldin A, which inhibits organello- answering these and other questions dated. However, studies have shown genesis via the Golgi, blocks the form- may allow us to manipulate the formation an important role for ABCA12 (Akiyama, ation of LB (Feingold, 2007). In this issue, of LBs and improve barrier function. 2011). ABCA12 is a member of the Tarutani et al. (2012) provide additional ABCA subfamily of transporters, which data demonstrating the importance of are involved in the transport of a variety the Golgi in the formation of LBs. This CONFLICT OF INTEREST The author states no conflict of interest. of lipids. Loss-of-function mutations in group recently identified a novel anion ABCA12 have been shown to cause channel, Golgi pH Regulator (GPHR), harlequin ichthyosis, and milder mis- which is critical for Golgi acidification. ACKNOWLEDGEMENTS sense mutations cause a severe lamellar In the current article, they used a Cre- Over the years, our research has been supported by ichthyosis phenotype (Akiyama, 2011). loxP system to disrupt the expression of NIH grants, which were administered by the Northern California Institute for Research and ABCA12 mutations lead to a decrease GPHR, specifically in the skin. Although Education, and with resources of the Veterans in LB contents, a decrease in lamellar a number of cutaneous abnormalities Affairs Medical Center, San Francisco, California. membranes in the extracellular spaces of were noted, of particular interest was the stratum corneum, and loss-of-perme- a decrease in the expression of several REFERENCES ability barrier function, which in harlequin lamellar body markers, including TGN46, Aberg KM, Man MQ, Gallo RL et al. (2008) Co- ichthyosis can result in neonatal lethality KLK7, and sphingomyelinase. More- regulation and interdependence of the mam- (Akiyama, 2011). Biochemically, the over, electron microscopy revealed that malian epidermal permeability and antimicro- absence of ABCA12 is characterized by the normal internal membrane structure bial barriers. J Invest Dermatol 128:917–25 the accumulation of glucosylceramides of the lamellar bodies was markedly redu- Akiyama M (2011) The roles of ABCA12 in keratino- cyte differentiation and lipid barrier formation in with a reduction in ceramides (Akiyama, ced, with some empty lamellar bodies the epidermis. Dermato Endocrinol 3:107–12 2011). These studies demonstrate a critical visible. As expected, given the abnormal Braff MH, Di Nardo A, Gallo RL (2005) Keratino- role for ABCA12 in mediating the transport lamellar body appearance, the resultant cytes store the antimicrobial peptide catheli- of glucosylceramides into LBs and the bilayer lamellar structures in the extra- cidin in lamellar bodies. J Invest Dermatol subsequent formation of mature LBs and cellular spaces of the stratum corneum 124:394–400 normal barrier function. How cholesterol were decreased in number and abnormal Capon F, Burden AD, Trembath RC et al. (2012) Psoriasis and other complex trait dermatoses: and phospholipids are transported into LBs in appearance. Moreover, transepidermal from Loci to functional pathways. J Invest remains to be elucidated. ABCG1, another water loss was increased in mice defi- Dermatol 132:915–22

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Elias PM, Choi EH (2005) Interactions among Jiang YJ, Lu B, Tarling EJ et al. (2010) Regulation of modulating the fur color of mice. Soon stratum corneum defensive functions. Exp ABCG1 expression in human keratinocytes thereafter, studies on the functionality and murine epidermis. JLipidRes51:3185–95 Dermatol 14:719–26 of MC1R variants were carried out in Elias PM, Cullander C, Mauro T et al. (1998) The Oren A, Ganz T, Liu L et al. (2003) In human humans. Population studies revealed secretory granular cell: the outermost granular epidermis, beta-defensin 2 is packaged in cell as a specialized secretory cell. J Investig lamellar bodies. Exp Mol Pathol 74:180–2 that several MC1R variants are associ- Dermatol Symp Proc/Soc Invest Dermatol Rassner U, Feingold KR, Crumrine DA et al. (1999) ated with red hair and fair skin, desig- 3:87–100 Coordinate assembly of lipids and enzyme nated as red hair color (RHC) and fair Feingold KR (2007) Thematic review series: skin proteins into epidermal lamellar bodies. Tissue skin variants. Interestingly, the variant Cell 31:489–98 lipids. The role of epidermal lipids in cuta- alleles differ in their penetrance concern- neous permeability barrier homeostasis. Tarutani M, Nakajima K, Uchida Y et al. (2012) J Lipid Res 48:2531–46 GPHR-dependent functions of the Golgi ing the RHC phenotype (Sturm, 2002). Irvine AD, McLean WH, Leung DY (2011) Filag- apparatus are essential for the formation of The common variants R151C, R160W, grin mutations associated with skin and aller- lamellar granules and the skin barrier. J Invest and D294H and the rarely occurring gic diseases. N Engl J Med 365:1315–27 Dermatol 132:2019–25 variants D84E and R142H are strongly associated with the red hair phenotype in the Caucasian population, with odds See related article on pg 2026 ratios of 50- to 120-fold (referred to as (strong) R variants). The weak RHC alleles V60L, V92M, and R163Q have odds ratios for red hair between 2 and 6 Melanocortin 1 Receptor Function: and are therefore considered to be (weak) r variants. Soon after the corre- Shifting Gears from Determining Skin lations were observed between MC1R variants and the RHC phenotype, asso- and Nevus Phenotype to Fetal Growth ciations were observed between these Nelleke A. Gruis1 and Remco van Doorn1 variants and other skin-related pheno- types, such a risk of developing mela- Variants in the MC1R gene influence skin pigmentation and thereby modulate noma and non-melanoma skin cancer, risk of melanoma and basal and squamous cell carcinoma. In this issue, Kinsler as well as freckles (Sturm, 2002). Interest- et al. report an association between the MC1R genotype and the development ingly, associated odds ratios increased of congenital melanocytic nevi. Further, higher birth weight was observed in when more RHC variants were present carriers of MC1R variants, suggesting a role for the melanocortin network in in the genotype, with homozygous R fetal growth. variants conferring the highest risk. Despite the fact that more than 100 Journal of Investigative Dermatology (2012) 132, 1953–1955. doi:10.1038/jid.2012.216 variants in the MC1R gene have been identified to date, the consequences of these variants on the physiological func- Melanocortin 1 receptor functioning and Activation of MC1R by a-MSH leads tion of MC1R have been defined only genetic variants to an increase of cAMP, ultimately partially (Dessinioti et al., 2011). RHC The human MC1R gene, located on leading to complete activation of the variants R151C, R160W, and D294H chromosome 16q24.3, is highly poly- promoter of the microphthalmia tran- have been defined as strong RHC (R) morphic. The gene encodes for a G scription factor (MITF) gene. MITF has a variants based not only on their signifi- protein–coupled melanocortin 1 receptor key role in the control of melanogenesis, cant associations with specific pheno- that is expressed in melanocytes and other leading to increased transcription of typic features, such as red hair, fair cell types that reside in the skin, including a range of genes including TYR and skin, and freckling, but also on their keratinocytes and fibroblasts, as well as TYRP1, which are involved in the con- diminished receptor function, reduced a cells of the immune system. trol of the relative and absolute amounts response to -MSH, and reduced func- The major agonists of MC1R are clea- of eumelanin and pheomelanin pigment tional coupling of MC1R to adenylate vage products of proopiomelanocortin, in the skin. The MITF transcription factor cyclase in vitro. The functional relevance and they include the melanocyte-stimu- has many other transcriptional targets, of the weaker (low penetrant) RHC (r) lating hormones (MSHs) and adrenocor- including BCL2, MET, and HIF1A (Cheli variants, such as V60L, V92M, and ticotrophin. In particular, MC1R has high et al., 2010). Robbins et al. (1993) R163Q, is still a matter of debate, with affinity for a-MSH, which acts in an first described the association of MC1R some reports pointing to a minor signal- autocrine and paracrine manner. variants and receptor functionality in ing impairment, and others showing a behavior similar to that of wild-type MC1R (Dessinioti et al., 2011). One 1Skin Research Laboratory, LUMC, Leiden, The Netherlands report suggested that the V92M substitu- Correspondence: Nelleke A. Gruis, Skin Research Laboratory, LUMC, PO Box 9600, Room T-2-34, Post tion reduces the binding affinity of MC1R Code S2-P, Leiden, 2300 RC, The Netherlands. E-mail: [email protected] for a-MSH, whereas another found no

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