Oncotarget

Research Papers: Immunology:

Activation of human mast cells by retrocyclin and protegrin highlight their immunomodulatory and antimicrobial properties

Kshitij Gupta, Akhil Kotian, Hariharan Subramanian, Henry Daniell and Hydar Ali _

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Oncotarget. 2015; 6:28573-28587. https://doi.org/10.18632/oncotarget.5611

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Abstract

Kshitij Gupta1, Akhil Kotian2, Hariharan Subramanian1, Henry Daniell2 and Hydar Ali1

1 Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

2 Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

Correspondence to:

Hydar Ali, email:

Henry Daniell, email:

Keywords: antimicrobial peptides, mast cells, retrocyclin, protegrin, chloroplast, MrgX2, Immunology and Microbiology Section, Immune response, Immunity

Received: July 04, 2015 Accepted: August 30, 2015 Published: September 10, 2015

Abstract

Preclinical evaluation of Retrocyclins (RC-100, RC-101) and Protegrin-1 (PG-1) antimicrobial peptides (AMPs) is important because of their therapeutic potential against bacterial, fungal and viral infections. Human mast cells (HMCs) play important roles in host defense and wound healing but the abilities of retrocyclins and protegrin-1 to harness these functions have not been investigated. Here, we report that chemically synthesized RC-100 and PG-1 caused calcium mobilization and degranulation in HMCs but these responses were not blocked by an inhibitor of formyl peptide receptor-like 1 (FPRL1), a known receptor for AMPs. However, RC-100 and PG-1 induced degranulation in rat basophilic leukemia (RBL-2H3) cells stably expressing Mas related G protein coupled receptor X2 (MrgX2). Chemical synthesis of these AMPs is prohibitively expensive and post-synthesis modifications (cyclization, disulfide bonds, folding) are inadequate for optimal antimicrobial activity. Indeed, we found that synthetic RC-100, which caused mast cell degranulation via MrgX2, did not display any antimicrobial activity. Green-fluorescent protein (GFP)-tagged RC-101 (analog of RC-100) and GFP-tagged PG-1 purified from transgenic plant chloroplasts killed bacteria and induced mast cell degranulation. Furthermore, GFP-PG1 bound specifically to RBL-2H3 cells expressing MrgX2. These findings suggest that retrocyclins and protegrins activate HMCs independently of FPRL1 but via MrgX2. Harnessing this novel feature of AMPs to activate mast cell’s host defense/wound healing properties in addition to their antimicrobial activities expands their clinical potential. Low cost production of AMPs in plants should facilitate their advancement to the clinic overcoming major hurdles in current production systems.


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