Review: Human antimicrobial proteins — effectors of innate immunity

Harder, Jürgen; Gläser, Regine; Schröder, Jens‐Michael

doi:10.1177/0968051907088275

Cited by 93 publications

(83 citation statements)

References 268 publications

(308 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This together with other proteins and enzymatic activities substantially augments the mechanical stability of keratin filaments (2,9,11). Thus, filaggrin is central to the development of an efficient skin barrier in combination with other processes that result in the generation of the cornified envelope (2,3,5,12,13), including the strengthening of cell-cell contacts by the maturation of desmosomes to corneodesmosomes (3,5,8,9,14,15), the formation of an lipid envelope (8,9,16,17), and the production of an antimicrobial barrier by synthesizing antimicrobial peptides (AMPs) and fatty acids (9,16,(18)(19)(20)(21).…”

mentioning

confidence: 99%

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Hänel

Pfaff

Cornelissen

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Atopic dermatitis, a chronic inflammatory skin disease with increasing prevalence, is closely associated with skin barrier defects. A cytokine related to disease severity and inhibition of keratinocyte differentiation is IL-31. To identify its molecular targets, IL-31–dependent gene expression was determined in three-dimensional organotypic skin models. IL-31–regulated genes are involved in the formation of an intact physical skin barrier. Many of these genes were poorly induced during differentiation as a consequence of IL-31 treatment, resulting in increased penetrability to allergens and irritants. Furthermore, studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following s.c. administration of IL-31. We identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1R antagonist, blocked the IL-31 effects on skin differentiation. In addition to the effects on the physical barrier, IL-31 stimulated the expression of antimicrobial peptides, thereby inhibiting bacterial growth on the three-dimensional organotypic skin models. This was evident already at low doses of IL-31, insufficient to interfere with the physical barrier. Together, these findings demonstrate that IL-31 affects keratinocyte differentiation in multiple ways and that the IL-1 cytokine network is a major downstream effector of IL-31 signaling in deregulating the physical skin barrier. Moreover, by interfering with IL-31, a currently evaluated drug target, we will have to consider that low doses of IL-31 promote the antimicrobial barrier, and thus a complete inhibition of IL-31 signaling may be undesirable.

show abstract

mentioning

confidence: 99%

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Hänel

Pfaff

Cornelissen

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…-Defensins, small molecular peptides with antimicrobial activity, represent one of the major components of the antimicrobial defense of the innate immune system (1,2). As the outermost barrier, the skin is constantly exposed to microbial attacks.…”

mentioning

confidence: 99%

Induction of Regulatory T Cells by a Murine β-Defensin

Navid

Boniotto

Walker

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

β-Defensins are antimicrobial peptides of the innate immune system produced in the skin by various stimuli, including proinflammatory cytokines, bacterial infection, and exposure to UV radiation (UVR). In this study we demonstrate that the UVR-inducible antimicrobial peptide murine β-defensin-14 (mBD-14) switches CD4+CD25− T cells into a regulatory phenotype by inducing the expression of specific markers like Foxp3 and CTLA-4. This is functionally relevant because mBD-14–treated T cells inhibit sensitization upon adoptive transfer into naive C57BL/6 mice. Accordingly, injection of mBD-14, comparable to UVR, suppresses the induction of contact hypersensitivity and induces Ag-specific regulatory T cells (Tregs). Further evidence for the ability of mBD-14 to induce Foxp3+ T cells is provided using DEREG (depletion of Tregs) mice in which Foxp3-expressing cells can be depleted by injecting diphtheria toxin. mBD-14 does not suppress sensitization in IL-10 knockout mice, suggesting involvement of IL-10 in mBD-14–mediated immunosuppression. However, unlike UVR, mBD-14 does not appear to mediate its immunosuppressive effects by affecting dendritic cells. Accordingly, UVR-induced immunosuppression is not abrogated in mBD-14 knockout mice. Together, these data suggest that mBD-14, like UVR, has the capacity to induce Tregs but does not appear to play a major role in UVR-induced immunosuppression. Through this capacity, mBD-14 may protect the host from microbial attacks on the one hand, but tame T cell-driven reactions on the other hand, thereby enabling an antimicrobial defense without collateral damage by the adaptive immune system.

show abstract

“…This, along with other results showing that hBD-2 is induced as a result of inflammation via MAPK or NF〉 (5) while hBD-3 is activated through epidermal growth factor receptor (13,14), strongly suggests that the latter is more involved in wound healing while the former plays a more active role in inhibiting microbial invasion during mucosal-barrier disruption (15)(16)(17). Moreover, in addition to their antimicrobial properties (18,19), both peptides have been shown to act as chemokines in recruiting lymphoid and myeloid cells from the bloodstream (20).…”

mentioning

confidence: 79%

“…Tissue acquisition for primary cell isolation was conducted in accordance with our Institutional Review Board (IRB)-approved protocol (NHR- [15][16][17][18][19] for the use of discarded tissue. Primary HOECs were expanded from tissues overlying impacted third molars, as previously described (24), and grown as monolayers to ϳ70% confluence.…”

Section: Methodsmentioning

confidence: 99%

FAD-I, a Fusobacterium nucleatum Cell Wall-Associated Diacylated Lipoprotein That Mediates Human Beta Defensin 2 Induction through Toll-Like Receptor-1/2 (TLR-1/2) and TLR-2/6

Bhattacharyya¹,

Ghosh²,

Shokeen

et al. 2016

Infect Immun

View full text Add to dashboard Cite

We previously identified a cell wall-associated protein from Fusobacterium nucleatum, a Gram-negative bacterium of the oral cavity, that induces human beta defensin 2 (hBD-2) in primary human oral epithelial cells (HOECs) and designated it FAD-I (Fusobacterium-associated defensin inducer). Here, we report differential induction of hBD-2 by different strains of F. nucleatum; ATCC 25586 and ATCC 23726 induce significantly more hBD-2 mRNA than ATCC 10953. Heterologous expression of plasmid-borne fadI from the highly hBD-2-inducing strains in a ⌬fadI mutant of ATCC 10953 resulted in hBD-2 induction to levels comparable to those of the highly inducing strains, indicating that FAD-I is the principal F. nucleatum agent for hBD-2 induction in HOECs. Moreover, anti-FAD-I antibodies blocked F. nucleatum induction of hBD-2 by more than 80%. Recombinant FAD-I (rFAD-I) expressed in Escherichia coli triggered levels of hBD-2 transcription and peptide release in HOECs similar to those of native FAD-I (nFAD-I) isolated from F. nucleatum ATCC 25586. Tandem mass spectrometry revealed a diacylglycerol modification at the cysteine residue in position 16 for both nFAD-I and rFAD-I. Cysteine-to-alanine substitution abrogated FAD-I's ability to induce hBD-2. Finally, FAD-I activation of hBD-2 expression was mediated via both Toll-like receptor-1/2 (TLR-1/2) and TLR-2/6 heterodimerization. Microbial molecules like FAD-I may be utilized in novel therapeutic ways to bolster the host innate immune response at mucosal surfaces.T he epithelial surfaces of the oral cavity are sites of active bacterial colonization. While colonizing, certain bacteria promote activation of human beta defensin (hBD) expression in the oral mucosa (1-3). By virtue of their antimicrobial and immunoregulatory properties, these epithelial-cell-derived innate response peptides contribute to the homeostasis between the bacterium and the host (4). Human beta defensin 2 (hBD-2) and hBD-3 are the two inducible members of the hBD peptide family that we and others have described in the oral cavity (1, 5-10). Interestingly, while hBD-3 is associated with the highly proliferating, nondifferentiated stratum basale of the oral mucosa, hBD-2 is compartmentalized in the more superficial stratum spinosum and stratum granulosum; i.e., nonproliferating yet differentiating regions of the oral mucosa (11,12). This, along with other results showing that hBD-2 is induced as a result of inflammation via MAPK or NF〉 (5) while hBD-3 is activated through epidermal growth factor receptor (13, 14), strongly suggests that the latter is more involved in wound healing while the former plays a more active role in inhibiting microbial invasion during mucosal-barrier disruption (15-17). Moreover, in addition to their antimicrobial properties (18, 19), both peptides have been shown to act as chemokines in recruiting lymphoid and myeloid cells from the bloodstream (20).Fusobacterium nucleatum, a ubiquitous Gram-negative bacterium of the human oral cavity, has been extensively studied for its propert...

show abstract

Review: Human antimicrobial proteins — effectors of innate immunity

Cited by 93 publications

References 268 publications

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Induction of Regulatory T Cells by a Murine β-Defensin

FAD-I, a Fusobacterium nucleatum Cell Wall-Associated Diacylated Lipoprotein That Mediates Human Beta Defensin 2 Induction through Toll-Like Receptor-1/2 (TLR-1/2) and TLR-2/6

Contact Info

Product

Resources

About