Introduction: Psoriasis is a chronic immune-mediated inflammatory disease. Human cathelicidin (hCAP18/LL37) has been elucidated recently as a modulator of inflammation in the affected skin. Vitamin D may induce expression of this antimicrobial peptide. Our trial aimed to study the circulating level of hCAP18/LL-37 and to explore its relationship with the severity of psoriasis.
Material and Methods: 79 patients with moderate to severe psoriasis (PASI >10) were included in a retrospective analysis. Stored serum samples were used for assessment of 25-hydroxyvitamin D - 25(OH)D and to measure the circulating human cathelicidin (LL-37).
Results: In a study group of 79 patients we assessed mean level of 25(OH)D of 30.25 nmol/l (95% CI 25.87 - 34.62 nmol/l). Mean circulating cathelicidin was 27.17 ng/ml (95% CI 21.52 - 32.83 ng/ml). Only 8.9% of patients had LL-37 level > 54 ng/ml. Although circulating LL-37 was lower in severe psoriasis than in moderate psoriasis (24.33 ng/ml vs. 31.14 ng/ml), the variation is nonsignificant. We further evaluated the association of LL-37 with both PASI score and 25(OH)D concentration in the subgroup of patients with vitamin D deficiency (n=39). It was interesting to find a significant correlation between the level of LL-37 and 25(OH)D (r=0.38, p=0.017) and inverse association between the level of LL-37 and PASI (r= -0.30, p=0.06).
Conclusion: In this pilot trial we assessed low serum levels of cathelicidin antimicrobial peptide in the patients with psoriasis. LL-37 may be discussed as related to PASI and 25(OH)D in a subgroup of psoriatic patients with vitamin D deficiency.
Bibliography
Enamandram M, Kimball AB. Psoriasis epidemiology: the interplay of genes and the environment. J Invest Dermatol. 2013; 133(2): 287–9.
Batycka-Baran, Maj J, Wolf R, Szepietowski JC. The new insight into the role of antimicrobial proteins-alarmins in the immunopathogenesis of psoriasis. J Immunol Res. 2014; Article ID 628289.
Morizane S, Gallo RL. Antimicrobial peptides in the pathogenesis of psoriasis. J Dermatol 2012; 39(3): 225–30.
Méndez-Samperio P. The human cathelicidin hCAP18/LL-37: a multifunctional peptide involved in mycobacterial infections. Peptides. 2010; 31(9): 1791–8.
Zaiou M, Nizet V, Gallo RL. Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. J Invest Dermatol. 2003; 120(5): 810–6.
Frohm M, Agerberth B, Ahangari G, Stahle-Backdahl M, Liden S, Wigzell H, et al. The Expression of the Gene Coding for the Antibacterial Peptide LL-37 Is Induced in Human Keratinocytes during Inflammatory Disorders. J Biol Chem. 1997; 272(24): 15258–63.
De Yang, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med. 2000; 192(7): 1069–74.
Koczulla R, von Degenfeld G, Kupatt C, Krötz F, Zahler S, Gloe T, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111(11):1665–72.
Braff MH, Hawkins MA, Nardo AD, Lopez-Garcia B, Howell MD, Wong C, et al. Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities. J Immunol. 2005; 174(7): 4271–8.
Morioka Y, Yamasaki K, Leung D, Gallo RL. Cathelicidin antimicrobial peptides inhibit hyaluronan-induced cytokine release and modulate chronic allergic dermatitis. J Immunol. 2008; 181(6): 3915–22.
Mookherjee N, Brown KL, Bowdish DME, Doria S, Falsafi R, Hokamp K, et al. Modulation of the TLR-Mediated Inflammatory Response by the Endogenous Human Host Defense Peptide LL-37. J Immunol. 2006; 176(4): 2455–64.
Mookherjee N, Wilson HL, Doria S, Popowych Y, Falsafi R, Yu JJ, et al. Bovine and human cathelicidin cationic host defense peptides similarly suppress transcriptional responses to bacterial lipopolysaccharide. J Leukoc Biol. 2006; 80(6): 1563–74.
Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang Y-H, Homey B, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007; 449 (7162): 564–9.
Lande R, Botti E, Jandus C, Dojcinovic D, Fanelli G, Conrad C, et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat Commun. 2014; 5: 5621.
Dixon BM, Barker T, McKinnon T, Cuomo J, Frei B, Borregaard N, et al. Positive correlation between circulating cathelicidin antimicrobial peptide (hCAP18/LL-37) and 25-hydroxyvitamin D levels in healthy adults. BMC Res Notes. 2012; 5: 575.
Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol [Internet]. 1985; 13(3): 450–6.
Krasowski MD. Pathology consultation on vitamin D testing. Am J Clin Pathol. 2011; 136(4): 507–14.
Nair R, Maseeh A. Vitamin D: The “sunshine” vitamin. J Pharmacol Pharmacother. 2012; 3(2): 118–26.
Gisondi P, Rossini M, Di Cesare a, Idolazzi L, Farina S, Beltrami G, et al. Vitamin D status in patients with chronic plaque psoriasis. Br J Dermatol. 2012;1 66(3): 505–10.
Ricceri F, Pescitelli L, Tripo L, Prignano F. Deficiency of serum concentration of 25-hydroxyvitamin D correlates with severity of disease in chronic plaque psoriasis. J Am Acad Dermatol. 2013; 68(3): 511–2.
Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006; 311(5768): 1770–3.
Hata TR, Kotol P, Jackson M, Nguyen M, Paik A, Udall D, et al. Administration of oral vitamin D induces cathelicidin production in atopic individuals. J Allergy Clin Immunol. 2008; 122(4): 829–31.
Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB. 2005; 19(9): 1067–77.
Jeng L, Yamshchikov A V, Judd SE, Blumberg HM, Martin GS, Ziegler TR, et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009] ;7:28.
Alvarez-Rodriguez L, Lopez-Hoyos M, Garcia-Unzueta M, Amado JA, Cacho PM, Martinez-Taboada VM. Age and low levels of circulating vitamin D are associated with impaired innate immune function. J Leukoc Biol. 2012; 91(5): 829–38.
Yamshchikov A V, Kurbatova E V, Kumari M, Blumberg HM, Ziegler TR, Ray SM, et al. Vitamin D status and antimicrobial peptide cathelicidin (LL-37) concentrations in patients with active pulmonary tuberculosis. Am J Clin Nutr. 2010; 92(3): 603–11.
Gombart AF, Bhan I, Borregaard N, Tamez H, Camargo CA, Koeffler HP, et al. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clin Infect Dis. 2009; 48(4): 418-24.
Quraishi SA, De Pascale G, Needleman JS, Nakazawa H, Kaneki M, Bajwa EK, et al. Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis: A Randomized, Placebo-Controlled Trial. Crit Care Med. 2015; 43(9): 1928-37.
Ye Y, Carlsson G, Karlsson-Sjöberg JMT, Borregaard N, Modéer TU, Andersson ML, et al. The antimicrobial propeptide hCAP-18 plasma levels in neutropenia of various aetiologies: a prospective study. Sci Rep. 2015; 5: 11685.
Yang Y-M, Guo Y-F, Zhang H-S, Sun T-Y. Antimicrobial peptide LL-37 circulating levels in chronic obstructive pulmonary disease patients with high risk of frequent exacerbations. J Thorac Dis. 2015; 7(4): 740-5.
Honda JR, Connick E, MaWhinney S, Chan ED, Flores SC. Plasma LL-37 correlates with vitamin D and is reduced in human immunodeficiency virus-1 infected individuals not receiving antiretroviral therapy. J Med Microbiol. 2014; 63: 997-1003.
Zhao H, Yan H, Yamashita S, Li W, Liu C, Chen Y, et al. Acute ST-Segment Elevation Myocardial Infarction is Associated with Decreased Human Antimicrobial Peptide LL-37 and Increased Human Neutrophil Peptide-1 to 3 in Plasma. J Atheroscler Thromb. 2012; 19(4): 357-68.
Iacob SA, Panaitescu E, Iacob DG, Cojocaru M. The human cathelicidin LL37 peptide has high plasma levels in B and C hepatitis related to viral activity but not to 25-hydroxyvitamin D plasma level. Rom J Intern Med; 2012:
(3): 217–23.
Hwang YJ, Jung HJ, Kim MJ, Roh NK, Jung JW, Lee YW, et al. Serum levels of LL-37 and inflammatory cytokines in plaque and guttate psoriasis. Mediators Inflamm. 2014; Article ID 268257.
Al-Mutairi N, El Eassa B, Nair V. Measurement of vitamin D and cathelicidin (LL-37) levels in patients of psoriasis with co-morbidities. Indian J Dermatol Venereol Leprol. 2013; 79(4): 492–6.
Kanda N, Ishikawa T, Kamata M, Tada Y, Watanabe S. Increased serum leucine, leucine-37 levels in psoriasis: positive and negative feedback loops of leucine, leucine-37 and pro- or anti-inflammatory cytokines. Hum Immunol. 2010; 71(12): 1161–71.
Wang Y. Apolipoprotein A-I Binds and Inhibits the Human Antibacterial/Cytotoxic Peptide LL-37. J Biol Chem. 1998; 273(50): 33115–8.
Bhan I, Camargo CA, Wenger J, Ricciardi C, Ye J, Borregaard N, et al. Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. J Allergy Clin Immunol. 2011; 127(5): 1302–4.