Nat Med. 2007 Aug;13(8):975-80. Epub 2007 Aug 5. Links

Comment in:

Nat Med. 2007 Aug;13(8):904-6.

Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, Dorschner RA, Bonnart C, Descargues P, Hovnanian A, Morhenn VB, Gallo RL.

Division of Dermatology, University of California, San Diego, and VA San Diego Health Care System, 3350 La Jolla Village Drive, San Diego, California 92161, USA.

 

Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.

 

PMID: 17676051 [PubMed - indexed for MEDLINE]

 

J Invest Dermatol. 2007 Oct 18; [Epub ahead of print] Links

Co-Regulation and Interdependence of the Mammalian Epidermal Permeability and Antimicrobial Barriers.Aberg KM, Man MQ, Gallo RL, Ganz T, Crumrine D, Brown BE, Choi EH, Kim DK, Schröder JM, Feingold KR, Elias PM.

[1] 1Dermatology and Medical (Metabolism) Services, Veterans Affairs Medical Center, University of California, San Francisco, California, USA [2] 2Departments of Dermatology and Medicine, University of California, San Francisco, California, USA.

 

Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), beta-defensin 2 (hBD2), and the carboxypeptide cleavage product of human cathelicidin (hCAP18), LL-37, which are co-packaged along with lipids within epidermal lamellar bodies (LBs) before their secretion. Because of their colocalization, we hypothesized that AMP and barrier lipid production could be coregulated by altered permeability barrier requirements. mRNA and immunostainable protein levels for mBD3 and cathelin-related antimicrobial peptide (CRAMP) (murine homologues of hBD2 and LL-37, respectively) increase 1-8 hours after acute permeability barrier disruption and normalize by 24 hours, kinetics that mirror the lipid metabolic response to permeability barrier disruption. Artificial permeability barrier restoration, which inhibits the lipid-synthetic response leading to barrier recovery, blocks the increase in AMP mRNA/protein expression, further evidence that AMP expression is linked to permeability barrier function. Conversely, LB-derived AMPs are also important for permeability barrier homeostasis. Despite an apparent increase in mBD3 protein, CRAMP-/- mice delayed permeability barrier recovery, attributable to defective LB contents and abnormalities in the structure of the lamellar membranes that regulate permeability barrier function. These studies demonstrate that (1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and (2) CRAMP is required for permeability barrier homeostasis.Journal of Investigative Dermatology advance online publication, 18 October 2007; doi:10.1038/sj.jid.5701099.

 

PMID: 17943185 [PubMed - as supplied by publisher]

 

J Immunol. 2007 Aug 15;179(4):2060-3. Links

Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin.Liu PT, Stenger S, Tang DH, Modlin RL.

Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

 

Host defense against intracellular pathogens depends upon innate and adaptive antimicrobial effector pathways. TLR2/1-activation of monocytes leads to the vitamin D-dependent production of cathelicidin and, at the same time, an antimicrobial activity against intracellular Mycobacterium tuberculosis. To determine whether induction of cathelicidin was required for the vitamin D-triggered antimicrobial activity, the human monocytic cell line THP-1 was infected with M. tuberculosis H37Ra and then activated with the active vitamin D hormone 1,25-dihydroxyvitamin D(3) (1,25D(3)). 1,25D(3) stimulation resulted in antimicrobial activity against intracellular M. tuberculosis and expression of cathelicidin mRNA and protein. Using small interfering RNA (siRNA) specific for cathelicidin, 1,25D(3)-induced cathelicidin mRNA and protein expressions were efficiently knocked down, whereas a nonspecific siRNA control had little effect. Finally, 1,25D(3)-induced antimicrobial activity was completely inhibited in the presence of siRNA against cathelicidin, instead leading to enhanced intracellular growth of mycobacteria. These data demonstrate that cathelicidin is required for the 1,25D(3)-triggered antimicrobial activity against intracellular M. tuberculosis.

 

PMID: 17675463 [PubMed - indexed for MEDLINE]

 

Am J Rhinol. 2007 May-Jun;21(3):367-72. Links

Fungal allergens induce cathelicidin LL-37 expression in chronic rhinosinusitis patients in a nasal explant model.Ooi EH, Wormald PJ, Carney AS, James CL, Tan LW.

Department of Surgery-Otorhinolaryngology Head and Neck Surgery, University of Adelaide and Flinders University, Adelaide, Australia.

 

BACKGROUND: Fungus is thought to play an important role in some subgroups of chronic rhinosinusitis (CRS) patients with eosinophilic mucus (EMCRS). The cathelicidin LL-37 is an important innate defense peptide with antimicrobial activity but its responses in CRS and EMCRS patients have not been established. We investigated the innate immune responses of LL-37 in nasal tissue from CRS and EMCRS patients to fungal allergen challenge. METHODS: The levels of LL-37 produced by nasal tissue and secreted in response to fungal allergen challenge were determined by a nasal tissue explant in vitro model. LL-37 mRNA and protein levels were quantified by real-time reverse-transcriptase-polymerase chain reaction and immunoassay methods. RESULTS: LL-37 mRNA expression in CRS, but not EMCRS patients, is significantly upregulated by Aspergillus (mean fourfold increase) and Alternaria (mean sixfold increase) extracts in a dose-response manner (p < 0.001). LL-37 peptide levels in the nasal tissue from CRS patients are increased in response to Alternaria (p < 0.05). In contrast, with EMCRS patients, the expression of LL-37 peptide in nasal tissue is increased with Aspergillus (p < 0.001) but is reduced with Alternaria. We also observed a trend where levels of secreted LL-37 were decreased with higher doses of Alternaria and Aspergillus extracts. CONCLUSION: LL-37 is significantly up-regulated at the mRNA and protein level in CRS patients in response to fungal allergens. However, EMCRS patients do not show increased LL-37 at either the mRNA or the protein level in response to Alternaria.

 

PMID: 17621825 [PubMed - indexed for MEDLINE]