Chemoattraction of Macrophages, T Lymphocytes, and Mast Cells Is Evolutionarily Conserved within the Human α-Defensin Family

Abstract

Human defensins are natural peptide antibiotics. On the basis of the position and bonding of six conserved cysteine residues, they are divided into two families, designated α- and β-defensins. Human α-defensins are expressed predominantly in neutrophils (human neutrophil peptides (HNP) 1–4) or intestinal Paneth cells (human defensins (HD) 5 and 6). Although α-defensins have been implicated in the pathogenesis of inflammatory bowel disease, their immunomodulatory functions are poorly understood. In the present study, HNP-1, HNP-3, and HD5 were found to be potent chemotaxins for macrophages but not dendritic cells using Gαi proteins and MAPK as signal transducers. α-Defensins were also chemoattractive for the human mast cell line HMC-1 but lacked, in contrast to β-defensins, the ability to induce intracellular calcium fluxes. Furthermore, HNP-1, HNP-3, and HD5 comparably mobilized naive as well as memory T lymphocytes. Using the protein kinase C (PKC) inhibitors GF109 and Gö6976, we observed a PKC-independent functional desensitization to occur between human α-defensins, which suggests a common receptor for HNP-1, HNP-3, and HD5 on immune cells. This α-defensin receptor was subject to heterologous desensitization by the PKC activator PMA and to PKC-dependent cross-desensitization by human β-defensins. Conversely, α-defensins desensitized β-defensin-mediated migration of immune cells in a PKC-dependent manner, suggesting unique receptors for both defensin families. Taken together, our observations indicate that chemoattraction of macrophages, T lymphocytes, and mast cells represents an immunomodulatory function which is evolutionarily conserved within the human α-defensin family and tightly regulated by β-defensins.

2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV

“…Importantly, this occurred at physiological (nanomolar) concentrations of 2-AG and AA and was associated with the release of LL-37 and α-defensins from cytochalasin B-treated neutrophils. Numerous events associated with the innate and adaptive immune responses are linked to antimicrobial peptides: they recruit and activate leukocytes [5][6][7][8][9][10][11][12][13], the complement cascade [87], and the phagocytosis by macrophages. Consequently, our data support that 2-AG and AA may be important physiological regulators of the innate and adaptive immune responses in humans.…”

“…α-Defensins are small, cationic peptides accounting for ~5% of neutrophil proteins, and LL-37 is an α-helix peptide containing 37 aa that originates from the C-terminal domain of the cathelicidin human cationic antimicrobial protein-18. In addition to their antimicrobial properties against viruses and bacteria [1][2][3][4], α-defensins and LL-37 recruit and activate leukocytes [5][6][7][8][9][10][11][12][13].…”

Manning the Barricades: Role of the Gut Epithelium in Crohn’s Disease

“…In addition to their antimicrobial activities, increasing evidence suggests that defensins play a significant role in innate and adaptive immunity. Such functions include chemoattraction and immune cell activation and promotion of cell proliferation, often involving interactions with cellular receptors (Aarbiou et al, 2002;Biragyn et al, 2002;Grigat et al, 2007;Yang et al, 1999). The capacity to chemoattractant monocytes was first described for HNPs (Territo et al, 1989).…”

Defensins: Potential Effectors in Autoimmune Rheumatic Disorders

“…T-cells that interact with antigen-presenting cells to promote adaptive immune responses [24] are attracted by defensins [13,15,16,25]. Costimulatory molecules on T-cells (i.e., CD28) are increased in response to HNP1-3 [26,27] and the secretion of various proinflammatory peptides is promoted [26,28].…”

“…For instance, monocytes (Mo), macrophages (MΦ) and immature dendritic cells (iDC) are attracted to sites of inflammation by defensins [12][13][14][15][16], where the secretion of proinflammatory cytokines by these cells is modulated, although there is still dispute to whether HNP1-3 are predominantly pro- [17,18] or anti-inflammatory [19][20][21]. Moreover, defensins have an impact on antigen presentation by influencing processes of differentiation: HNP1-3 was shown to inhibit M-CSF induced macrophage differentiation of monocytes [22], while maturation of iDC with upregulation of the co-stimulatory molecules CD80 and CD86 as well as MHCII is promoted by hBD3 [5,12,23].…”