Anti-inflammatory and Antibacterial Effects of Human Cathelicidin Active Fragment KR-12 in the Mouse Models of Colitis: a Novel Potential Therapy of Inflammatory Bowel Diseases

Overview

Journal Pharmacol Rep

Specialty Pharmacology

Date 2020 Nov 21

PMID 33219923

Citations 5

Authors

Natalia Fabisiak

Adam Fabisiak

Anna Chmielowiec-Korzeniowska

Leszek Tymczyna

Wojciech Kamysz

Radzislaw Kordek

Marta Bauer

Elzbieta Kamysz

Jakub Fichna

Affiliations

Soon will be listed here.

Abstract

Introduction: Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal tract disorders with complex etiology, with intestinal dysbiosis as the most prominent factor. In this study, we assessed the anti-inflammatory and antibacterial actions of the human cathelicidin LL-37 and its shortest active fragment, KR-12 in the mouse models of colitis.

Materials And Methods: Mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) and dextran sulfate sodium (DSS) were used in the study. The extent of inflammation was evaluated based on the macro- and microscopic scores, quantification of myeloperoxidase (MPO) activity and microbiological analysis of stool samples.

Results: A preliminary study with LL-37 and KR-12 (1 mg/kg, ip, twice daily) showed a decrease in macroscopic and ulcer scores in the acute TNBS-induced model of colitis. We observed that KR-12 (5 mg/kg, ip, twice daily) reduced microscopic and ulcer scores in the semi-chronic and chronic TNBS-induced models of colitis compared with inflamed mice. Furthermore, qualitative and quantitative changes in colonic microbiota were observed: KR-12 (5 mg/kg, ip, twice daily) decreased the overall number of bacteria, Escherichia coli and coli group bacteria. In the semi-chronic DSS-induced model, KR-12 attenuated intestinal inflammation as demonstrated by a reduction in macroscopic score and colon damage score and MPO activity.

Conclusions: We demonstrated that KR-12 alleviates inflammation in four different mouse models of colitis what suggests KR-12 and cathelicidins as a whole are worth being considered as a potential therapeutic option in the treatment of IBD.

Citing Articles

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Diminished Immune Response and Elevated Abundance in Gut Microbe Dubosiella in Mouse Models of Chronic Colitis with GBP5 Deficiency.

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Rivas-Santiago B, Jacobo-Delgado Y, Rodriguez-Carlos A Arch Immunol Ther Exp (Warsz). 2021; 69(1):25.

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References

Sobczak M, Fabisiak A, Murawska N, Wesolowska E, Wierzbicka P, Wlazlowski M . Current overview of extrinsic and intrinsic factors in etiology and progression of inflammatory bowel diseases. Pharmacol Rep. 2014; 66(5):766-75. DOI: 10.1016/j.pharep.2014.04.005. View

Shung D, Abraham B, Sellin J, Hou J . Medical and surgical complications of inflammatory bowel disease in the elderly: a systematic review. Dig Dis Sci. 2014; 60(5):1132-40. DOI: 10.1007/s10620-014-3462-2. View

Zhang H, Xia X, Han F, Jiang Q, Rong Y, Song D . Cathelicidin-BF, a Novel Antimicrobial Peptide from Bungarus fasciatus, Attenuates Disease in a Dextran Sulfate Sodium Model of Colitis. Mol Pharm. 2015; 12(5):1648-61. DOI: 10.1021/acs.molpharmaceut.5b00069. View

Akiyama T, Niyonsaba F, Kiatsurayanon C, Nguyen T, Ushio H, Fujimura T . The human cathelicidin LL-37 host defense peptide upregulates tight junction-related proteins and increases human epidermal keratinocyte barrier function. J Innate Immun. 2014; 6(6):739-53. PMC: 6742956. DOI: 10.1159/000362789. View

Koon H, Shih D, Chen J, Bakirtzi K, Hing T, Law I . Cathelicidin signaling via the Toll-like receptor protects against colitis in mice. Gastroenterology. 2011; 141(5):1852-63.e1-3. PMC: 3199285. DOI: 10.1053/j.gastro.2011.06.079. View

Yi H, Yu C, Zhang H, Song D, Jiang D, Du H . Cathelicidin-BF suppresses intestinal inflammation by inhibiting the nuclear factor-κB signaling pathway and enhancing the phagocytosis of immune cells via STAT-1 in weanling piglets. Int Immunopharmacol. 2015; 28(1):61-9. DOI: 10.1016/j.intimp.2015.05.034. View

Nishida A, Inoue R, Inatomi O, Bamba S, Naito Y, Andoh A . Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol. 2017; 11(1):1-10. DOI: 10.1007/s12328-017-0813-5. View

Kamysz E, Sikorska E, Jaskiewicz M, Bauer M, Neubauer D, Bartoszewska S . Lipidated Analogs of the LL-37-Derived Peptide Fragment KR12-Structural Analysis, Surface-Active Properties and Antimicrobial Activity. Int J Mol Sci. 2020; 21(3). PMC: 7036753. DOI: 10.3390/ijms21030887. View

Kamysz E, Sikorska E, Karafova A, Dawgul M . Synthesis, biological activity and conformational analysis of head-to-tail cyclic analogues of LL37 and histatin 5. J Pept Sci. 2012; 18(9):560-6. DOI: 10.1002/psc.2434. View

10.

Salaga M, Binienda A, Draczkowski P, Kosson P, Kordek R, Jozwiak K . Novel peptide inhibitor of dipeptidyl peptidase IV (Tyr-Pro-D-Ala-NH) with anti-inflammatory activity in the mouse models of colitis. Peptides. 2018; 108:34-45. DOI: 10.1016/j.peptides.2018.08.011. View

11.

Siczek K, Zatorski H, Chmielowiec-Korzeniowska A, Pulit-Prociak J, Smiech M, Kordek R . Synthesis and evaluation of anti-inflammatory properties of silver nanoparticle suspensions in experimental colitis in mice. Chem Biol Drug Des. 2016; 89(4):538-547. DOI: 10.1111/cbdd.12876. View

12.

Sood A, Midha V, Makharia G, Ahuja V, Singal D, Goswami P . The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol. 2009; 7(11):1202-9, 1209.e1. DOI: 10.1016/j.cgh.2009.07.016. View

13.

Kukla M, Adrych K, Dobrowolska A, Mach T, Regula J, Rydzewska G . Guidelines for infection in adults. Prz Gastroenterol. 2020; 15(1):1-21. PMC: 7089862. DOI: 10.5114/pg.2020.93629. View

14.

Yang X, Guo J, Sun L, Hu J, Shi Y, Zhang J . Assessment of different modalities for repeated tissue acquisition in diagnosing malignant biliary strictures: A two-center retrospective study. J Dig Dis. 2020; 22(2):102-107. DOI: 10.1111/1751-2980.12964. View

15.

Cui B, Feng Q, Wang H, Wang M, Peng Z, Li P . Fecal microbiota transplantation through mid-gut for refractory Crohn's disease: safety, feasibility, and efficacy trial results. J Gastroenterol Hepatol. 2014; 30(1):51-8. DOI: 10.1111/jgh.12727. View

16.

Paramsothy S, Paramsothy R, Rubin D, Kamm M, Kaakoush N, Mitchell H . Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis. 2017; 11(10):1180-1199. DOI: 10.1093/ecco-jcc/jjx063. View

17.

Tran D, Wang J, Ha C, Ho W, Mattai S, Oikonomopoulos A . Circulating cathelicidin levels correlate with mucosal disease activity in ulcerative colitis, risk of intestinal stricture in Crohn's disease, and clinical prognosis in inflammatory bowel disease. BMC Gastroenterol. 2017; 17(1):63. PMC: 5427565. DOI: 10.1186/s12876-017-0619-4. View

18.

Duplantier A, van Hoek M . The Human Cathelicidin Antimicrobial Peptide LL-37 as a Potential Treatment for Polymicrobial Infected Wounds. Front Immunol. 2013; 4:143. PMC: 3699762. DOI: 10.3389/fimmu.2013.00143. View

19.

Tai E, Wu W, Wang X, Wong H, Yu L, Li Z . Intrarectal administration of mCRAMP-encoding plasmid reverses exacerbated colitis in Cnlp(-/-) mice. Gene Ther. 2012; 20(2):187-93. DOI: 10.1038/gt.2012.22. View

20.

Hosoda H, Nakamura K, Hu Z, Tamura H, Reich J, Kuwahara-Arai K . Antimicrobial cathelicidin peptide LL‑37 induces NET formation and suppresses the inflammatory response in a mouse septic model. Mol Med Rep. 2017; 16(4):5618-5626. DOI: 10.3892/mmr.2017.7267. View