Pro-Dermcidin as an Emerging Regulator of Innate Immunity in Sepsis

Abstract

Human dermcidin (DCD) is synthesized as a 110-amino acid precursor (pre-dermcidin, pre-DCD) containing a 19-residue leader signal sequence, which is removed to produce a leader-less pro-domain-containing peptide termed as pro-dermcidin, pro-DCD. Pro-DCD can be secreted by human eccrine sweat glands and then cleaved into antimicrobial peptides, such as dermcidin (DCD). Emerging evidence suggests that pro-DCD has broader physiological roles beyond antimicrobial defense, potentially serving as a therapeutic agent for inflammatory diseases like sepsis. In this review, we summarize recent evidence supporting pro-DCD as a regulator of innate immunity in sepsis.

Keywords: anti-inflammatory; anti-microbial; innate immune cells; pro-dermcidin.

Figure 1

Amino acid sequence of human pro-dermcidin (pro-DCD) and epitope profile of anti-pro-DCD polyclonal antibodies. (A) Amino acid sequence and structural domains of human dermcidin precursor, pre-dermcidin (pre-DCD). (B) Amino acid sequence homology between human pro-DCD (20–110) and pro-DCD2 (20–121) isomer. (C) Sequence of synthetic peptides corresponding to various regions of human pro-DCD. (D) Epitope mapping of human pro-DCD-specific polyclonal antibodies by dot blotting analysis of recombinant pro-DCD and thirteen synthetic peptides (P1–P13) corresponding to different regions of pro-DCD. (E) Depiction of a peptide sequence (P9) that exhibits some homology to an inducible human acute-phase protein, serum amyloid A (SAA). Reprinted with permission from [9]. Copyright CC-BY, version 4.0.

Figure 2

Proposed role of pro-DCD in regulating innate immunity in sepsis. In response to severe bacterial infections, innate immune cells may upregulate and secrete pro-DCD into the bloodstream. Extracellular pro-DCD may confer protection against lethal sepsis partly by attenuating sepsis-induced dysregulated inflammatory injury and partly by facilitating systemic bacterial clearance possible via microtubule-associated protein 1A/1B-light chain 3 (LC3)-mediated phagocytosis and/or autophagy-dependent pathogen destruction. It remains to be determined whether pro-DCD loses its protective effects when LC3 is pharmacologically inhibited or genetically disrupted in future independent studies (“?”).