Intracellular Receptor for Human Host Defense Peptide LL-37 in Monocytes

Abstract

The human cationic host defense peptide LL-37 has a broad range of immunomodulatory, anti-infective functions. A synthetic innate defense regulator peptide, innate defense regulator 1 (IDR-1), based conceptually on LL-37, was recently shown to selectively modulate innate immunity to protect against a wide range of bacterial infections. Using advanced proteomic techniques, ELISA, and Western blotting procedures, GAPDH was identified as a direct binding partner for LL-37 in monocytes. Enzyme kinetics and mobility shift studies also indicated LL-37 and IDR-1 binding to GAPDH. The functional relevance of GAPDH in peptide-induced responses was demonstrated by using gene silencing of GAPDH with small interfering RNA (siRNA). Previous studies have established that the induction of chemokines and the anti-inflammatory cytokine IL-10 are critical immunomodulatory functions in the anti-infective properties of LL-37 and IDR-1, and these functions are modulated by the MAPK p38 pathway. Consistent with that, this study demonstrated the importance of the GAPDH interactions with these peptides since gene silencing of GAPDH resulted in impaired p38 MAPK signaling, downstream chemokine and cytokine transcriptional responses induced by LL-37 and IDR-1, and LL-37-induced cytokine production. Bioinformatic analysis, using InnateDB, of the major interacting partners of GAPDH indicated the likelihood that this protein can impact on innate immune pathways including p38 MAPK. Thus, this study has demonstrated a novel function for GAPDH as a mononuclear cell receptor for human cathelicidin LL-37 and immunomodulatory IDR-1 and conclusively demonstrated its relevance in the functioning of cationic host defense peptides.

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

“…5B), suggesting that cytoskeletal reorganization and endocytic uptake may be required for peptide activity. This raised the possibility that, like LL-37 and IDR-1 (41)(42)(43), peptide IDR-1002 may be actively internalized by cells and may act on intracellular, as well as cell-surface, targets.…”

Cathelicidin – Its Structure, Function and the Role in Autoimmune Diseases

“…LL-37 activity is much more frequently [32,40] boosted in cases of, e.g., psoriatic skin changes [10,42], SLE [18,25], contact dermatitis [28,34], bacterial infections [44,48,51], synovitis [19], chronic rhinitis [7], tracheal aspirates of newborn infants [7,32], cystic fibrosis [31], sarcoidosis [44,50] or cancer [7,48]. A decrease in the peptide activity was observed, e.g., in the atopic dermatitis [42], chronic epithelial ulceration [48,50], duodenum infections [7] and acute myeloid leukaemia [41].…”

“…The peptide has two disulphide bonds between the cystine C85-C96 and C107-C124 residues. Once protease 3 releases the C-terminal cation fragment from the hCAP-18 propeptide, the propeptide turns into LL-37 [32,34]. Next, there was a process alternative to observed action of protease 3, namely: the process of detaching hCAP-18 from ALL-38 which is an inactive hCAP-18 precursor, by prostate gastrixin protease in a suitable pH [11].…”

“…The only α-helical peptide occurring in humans is cathelicidin LL-37. It plays a vital role in the first line defence against infections and systemic invasions by pathogens in the place of an inflammation or wound [32,34].…”

“…They constitute a protection shield in the epithelium, where their expression may be induced during an infection or inflammation. AMPs' primary functions include: elimination of infectious pathogens [31,44,48], stimulation of cytokines' secretion [16,40,48] and of angiogenesis [7], inhibition of apoptosis [8,23,30], and activation of chemotactic [34,50,55], dendritic [12,15,32] and mast [7] cells. Meanwhile, these peptides participate in maturation and activation of autophagy [22], as well as in the process of wound healing [51].…”