The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands

Kändler, Kerstin; Shaykhiev, Renat; Kleemann, P. P.; Klescz, Frank; Lohoff, Michael; Vogelmeier, Claus; Bals, Robert

doi:10.1093/intimm/dxl107

Cited by 119 publications

(130 citation statements)

References 34 publications

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…Indeed, antimicrobial molecules such as LL-37, lactoferrin, and a-defensins can inhibit DC activation (33,54,56,57). In addition, elastase can induce TGF-b (32) and reduce proinflammatory cytokine production by moDC, thus promoting CD4 + lymphocyte T regulatory polarization (31).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells

Barrientos

Bignon

Gueguen

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Polymorphonuclear neutrophils (PMN) play a central role in inflammation and participate in its control, notably by modulating dendritic cell (DC) functions via soluble mediators or cell–cell contacts. Neutrophil extracellular traps (NETs) released by PMN could play a role in this context. To evaluate NET effects on DC maturation, we developed a model based on monocyte-derived DC (moDC) and calibrated NETs isolated from fresh human PMN. We found that isolated NETs alone had no discernable effect on moDC. In contrast, they downregulated LPS-induced moDC maturation, as shown by decreased surface expression of HLA-DR, CD80, CD83, and CD86, and by downregulated cytokine production (TNF-α, IL-6, IL-12, IL-23), with no increase in the expression of tolerogenic DC genes. Moreover, the presence of NETs during moDC maturation diminished the capacity of these moDC to induce T lymphocyte proliferation in both autologous and allogeneic conditions, and modulated CD4+ T lymphocyte polarization by promoting the production of Th2 cytokines (IL-5 and IL-13) and reducing that of Th1 and Th17 cytokines (IFN-γ and IL-17). Interestingly, the expression and activities of the lymphoid chemokine receptors CCR7 and CXCR4 on moDC were not altered when moDC matured in the presence of NETs. Together, these findings reveal a new role for NETs in adaptive immune responses, modulating some moDC functions and thereby participating in the control of inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells

Barrientos

Bignon

Gueguen

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…For example, LL-37 can activate macrophages to produce inflammatory cytokines in response to microbial stimuli and induce efficient phagocytosis of IgGopsonized bacteria (40). The peptide can modulate the differentiation of monocytes to DCs that promote the development of a Th subset expressing high levels of IFN-g and low/undetectable levels of IL-4/IL-5 (18), although maturation of the LL-37-differentiated DCs by several TLR ligands may be suppressed (19). In addition, it can enhance plasmacytoid DCs to produce IFN-a in response to self-DNA (41).When the infection recedes due to removal of pathogens and cellular debris by phagocytes, the levels of LL-37/GM-CSF in the local environment subside to homeostatic levels that facilitate differentiation of monocytes to macrophages with the "default" anti-inflammatory signature again.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its antimicrobial actions, LL-37 participates at the interface of innate and adaptive immunity by modulating cytokine and chemokine production by a range of cell types, chemoattracting various immune effector cells (14) and mesenchymal stem cells (15), regulating autophagy in conjunction with vitamin D (16), and stimulating angiogenesis and wound healing (17). Others reported that LL-37 enhances the GM-CSF/IL-4-driven differentiation of blood monocytes to immature DCs (18), whereas inhibiting the maturation of immature DCs by TLR ligands (19). Furthermore, this peptide enhances the responses of monocytes (and macrophages) to GM-CSF and IL-1b (20,21), but suppresses those to IFN-g (22), indicating that LL-37 affects the responses of mononuclear phagocytes to cytokines differentially.…”

mentioning

confidence: 99%

LL-37 Directs Macrophage Differentiation toward Macrophages with a Proinflammatory Signature

Does

Beekhuizen

Ravensbergen

et al. 2010

The Journal of Immunology

160

118

View full text Add to dashboard Cite

The human cathelicidin LL-37 has broad-spectrum antimicrobial activity. It also participates at the interface of innate and adaptive immunity by chemoattracting immune effector cells, modulating the production of a variety of inflammatory mediators by different cell types, and regulating the differentiation of monocytes into dendritic cells. In this study, we investigated the effects of LL-37 on the differentiation of human monocytes into anti-inflammatory macrophages (MΦ-2; driven by M-CSF) versus proinflammatory macrophages (MΦ-1; driven by GM-CSF) as well as on fully differentiated MΦ-1 and MΦ-2. Results revealed that monocytes cultured with M-CSF in the presence of LL-37 resulted in macrophages displaying a proinflammatory signature, namely, low expression of CD163 and little IL-10 and profound IL-12p40 production on LPS stimulation. The effects of LL-37 on M-CSF-driven macrophage differentiation were dose- and time-dependent with maximal effects observed at 10 μg/ml when the peptide was present from the start of the cultures. The peptide enhanced the GM-CSF–driven macrophage differentiation. Exposure of fully differentiated MΦ-2 to LL-37 for 6 d resulted in macrophages that produced less IL-10 and more IL-12p40 on LPS stimulation than control MΦ-2. In contrast, LL-37 had no effect on fully differentiated MΦ-1. Peptide mapping using a set of 16 overlapping 22-mer peptides covering the complete LL-37 sequence revealed that the C-terminal portion of LL-37 is responsible for directing macrophage differentiation. Our results furthermore indicate that the effects of LL-37 on macrophage differentiation required internalization of the peptide. Together, we conclude that LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.

show abstract

“…However, soluble mediators including IL-10, TSLP, TGF-b, NO and prostaglandins have also been implicated in the generation of an organ-specific microenvironment [18]. Also, the anti-microbial peptide LL-37 has been reported to alter DC phenotypes in the lung [33]. In our experiments we observe that soluble mediators can transfer the inhibitory potential of epithelial cells; however, cell contactdependent mechanisms might also been operative as suggested for intestinal epithelial cells and DC [31].…”

Section: Discussionmentioning

confidence: 99%

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

et al. 2008

View full text Add to dashboard Cite

The upper airways are prone to contact with pathogenic as well as non-pathogenic microbes, therefore immune recognition principles have to be tightly controlled. Here we show that human BEAS-2B bronchial epithelial cells inhibited secretion of the proinflammatory cytokines TNF-a and IL-12 by monocytes, macrophages and dendritic cells. This inhibitory effect could be transferred by supernatant of resting BEAS-2B cells and was also observed when primary murine tracheal epithelial cells were prepared. In contrast to inhibition of pro-inflammatory cytokine secretion epithelial cell-conditioned dendritic cells showed increased expression of IL-10 and arginase-1, thus displaying properties of alternative activation. Accordingly, Toll-like receptor-mediated up-regulation of CD40, CD86 and PD-L2 (CD273) on murine dendritic cells was reduced in the presence of bronchial epithelial cell supernatant. However, expression of negative regulatory PD-L1 (CD274) was increased and dendritic cell induced proliferation of T lymphocytes was diminished. Epithelial cells also showed a direct inhibitory effect on T lymphocyte proliferation and this was due to the constitutive secretion of TGF-b by bronchial epithelial cells. Moreover, epithelial cell-conditioned T lymphocytes showed increased differentiation towards IL-10-producing Tr1 cells. The results indicate that bronchial epithelial cells induce a noninflammatory microenvironment that regulates local immune homeostasis.

show abstract

The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands

Cited by 119 publications

References 34 publications

Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells

Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells

LL-37 Directs Macrophage Differentiation toward Macrophages with a Proinflammatory Signature

Airway epithelial cells modify immune responses by inducing an anti‐inflammatory microenvironment

Contact Info

Product

Resources

About