β‐Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved

Abstract

b-Defensins are natural peptide antibiotics whose immunomodulatory functions are poorly understood. In the present study, macrophages were found to migrate to human b-defensins (HBD)-1 to -4 using Ga i proteins as well as MAPK ERK, p38 and JNK as signal transducers. In addition, mast cells responded to HBD-1 to -4 with calcium fluxes as well as chemotaxis, which increased upon stimulation with IgE plus antigen or ionomycin. In contrast, human b-defensins were unable to induce migration of memory lymphocytes and dendritic cells (DC). Similar to HBD, the murine b-defensin (mBD)-8 mobilized macrophages and lacked the ability to recruit memory T cells. These findings were unexpected as CCR6 on memory T cells and DC has been previously observed to be a receptor for human b-defensins. In support of our findings, however, RBL-2H3 as well as 300.19 cells stably expressing CCR6 proved to be unresponsive to HBD-2 and -3. Intriguingly, our observation of a PKC-independent homologous desensitization between HBD-1 to -4 suggests a common receptor for HBD. In summary, chemoattraction of macrophages and mast cells is evolutionary conserved within the b-defensin family despite a considerable sequence variation and distinct antimicrobial activities. However, CCR6 is not a functional receptor for b-defensins.

CCL20 and β-Defensin-2 Induce Arrest of Human Th17 Cells on Inflamed Endothelium In Vitro under Flow Conditions

“…It is most likely due to differences in the experimental tools and/or conditions, and further studies are needed to determine the molecular factors that underlie this discrepancy. Nevertheless, the results obtained with CCR6-expressing T cells in the current study are in agreement with a previous report in the literature showing that hBD-2-induced chemotaxis in human monocyte-derived macrophages is not accompanied by the mobilization of Ca 2+ (51). A similar observation has been made in neutrophils showing that hBD2 was able to induce chemotaxis in a CCR6-dependent manner in the absence of mobilization of intracellular free Ca 2+ (52).…”

“…Values represent mean 6 SD of three experiments. no effect on the human mast cell line RBL-2H3 cells that had been stably transfected with the CCR6 gene (51). It is most likely due to differences in the experimental tools and/or conditions, and further studies are needed to determine the molecular factors that underlie this discrepancy.…”

Specific Binding and Chemotactic Activity of mBD4 and Its Functional Orthologue hBD2 to CCR6-expressing Cells

“…These results were independently verified by Taylor et al (16), demonstrating that single cysteine residues are needed for the chemotactic function of hBD3 and mBD14 but also that additional residues within the correct folded ␤-defensins are important for their chemotactic activity. Incorrect folding probably accounts for the recent report suggesting that ␤-defensins do not act through CCR6 (15). Our results clearly demonstrate that the specific binding of ␤-defensins to CCR6, FIGURE 6.…”

“…Although ␤-defensin usage of CCR6 as a chemotactic receptor is documented in many reports, it has not been shown whether ␤-defensins can specifically bind to CCR6. Furthermore, a more recent study using chemically synthesized ␤-defensins concluded that CCR6 was not involved in ␤-defensin-induced migration of leukocytes (15). Therefore, it remains somewhat controversial whether CCR6 can bind to ␤-defensins and mediate its chemotactic effects.…”

Defensins: Potential Effectors in Autoimmune Rheumatic Disorders

“…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].…”