Lamellar Bodies: the Key to and Cathepsins, Are Present in Lbs (Feingold, 2007)
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector COMMENTARY 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 À /À 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 À / À 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 À /À Clement Street, San Francisco, California 94121, USA. E-mail: [email protected] contents in CRAMP mice, other www.jidonline.org 1951 COMMENTARY 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.