Cell type-specific regulatory effects of glucocorticoids on cutaneous TLR2 expression and signalling

Su, Qi; Pfalzgraff, Anja; Weindl, Günther

doi:10.1016/j.jsbmb.2017.03.023

Cited by 8 publications

(9 citation statements)

References 69 publications

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“…Paradoxically, glucocorticoids have also been suggested to enhance inflammation and innate immune responses, particularly by upregulating TLR2 (40). An increase in TLR2 expression after GC administration was observed in many cell types, including epithelial cells (41–43), keratinocytes (44, 45), dendritic cells (10), and macrophages (11, 12, 45). Several studies showed that TLR ligands or inflammatory cytokines cooperate with GCs to induce TLR2 (12, 41–45).…”

Section: Discussionmentioning

confidence: 99%

“…An increase in TLR2 expression after GC administration was observed in many cell types, including epithelial cells (41–43), keratinocytes (44, 45), dendritic cells (10), and macrophages (11, 12, 45). Several studies showed that TLR ligands or inflammatory cytokines cooperate with GCs to induce TLR2 (12, 41–45). In line with our findings, Ji et al (12) reported that coadministration of the GC budesonide and LPS resulted in elevated TLR2 mRNA levels in human AMs, whereas TLR4 was not affected.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, TLR2 upregulation has been reported to be paralleled by immunosuppression (10, 12), which was confirmed by our study. The lack of cytokine release upon TLR2 stimulation of GC-treated cells has been explained by the downstream blockade of the TLR2 receptor signaling and lack of TLR2 heterodimerization partners (10, 12, 40, 45).…”

Section: Discussionmentioning

confidence: 99%

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Toll-Like Receptor 2 Release by Macrophages: An Anti-inflammatory Program Induced by Glucocorticoids and Lipopolysaccharide

et al. 2019

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Glucocorticoids (GCs) are widely prescribed therapeutics for the treatment of inflammatory diseases, and endogenous GCs play a key role in immune regulation. Toll-like receptors (TLRs) enable innate immune cells, such as macrophages, to recognize a wide variety of microbial ligands, thereby promoting inflammation. The interaction of GCs with macrophages in the immunosuppressive resolution phase upon prolonged TLR activation is widely unknown. Treatment of human alveolar macrophages (AMs) with the synthetic GC dexamethasone (Dex) did not alter the expression of TLRs −1, −4, and −6. In contrast, TLR2 was upregulated in a GC receptor-dependent manner, as shown by Western blot and qPCR. Furthermore, long-term lipopolysaccharide (LPS) exposure mimicking immunosuppression in the resolution phase of inflammation synergistically increased Dex-mediated TLR2 upregulation. Analyses of publicly available datasets suggested that TLR2 is induced during the resolution phase of inflammatory diseases, i.e., under conditions associated with high endogenous GC production. TLR2 induction did not enhance TLR2 signaling, as indicated by reduced cytokine production after treatment with TLR2 ligands in Dex- and/or LPS-primed AMs. Thus, we hypothesized that the upregulated membrane-bound TLR2 might serve as a precursor for soluble TLR2 (sTLR2), known to antagonize TLR2-dependent cell actions. Supernatants of LPS/Dex-primed macrophages contained sTLR2, as demonstrated by Western blot analysis. Activation of metalloproteinases resulted in enhanced sTLR2 shedding. Additionally, we detected full-length TLR2 and assumed that this might be due to the production of TLR2-containing extracellular vesicles (EVs). EVs from macrophage supernatants were isolated by sequential centrifugation. Both untreated and LPS/Dex-treated cells produced vesicles of various sizes and shapes, as shown by cryo-transmission electron microscopy. These vesicles were identified as the source of full-length TLR2 in macrophage supernatants by Western blot and mass spectrometry. Flow cytometric analysis indicated that TLR2-containing EVs were able to bind the TLR2 ligand Pam 3 CSK 4 . In addition, the presence of EVs reduced inflammatory responses in Pam 3 CSK 4 -treated endothelial cells and HEK Dual reporter cells, demonstrating that TLR2-EVs can act as decoy receptors. In summary, our data show that sTLR2 and full-length TLR2 are released by macrophages under anti-inflammatory conditions, which may contribute to GC-induced immunosuppression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Toll-Like Receptor 2 Release by Macrophages: An Anti-inflammatory Program Induced by Glucocorticoids and Lipopolysaccharide

et al. 2019

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“…Regarding TLR2, patients with SLE had a 56.6% lower expression in comparison to healthy controls. Although the regulating factors of the expression of TLR2 in SLE are unknown, glucocorticoids diminish its expression in keratinocytes and respiratory epithelial cells (39, 40). Previous studies had shown that patients with SLE had lower expression of TLR2 in monocytes in comparison to healthy controls (41), but this is the first study to describe it as a major risk factor for infection in lupus patients.…”

Section: Discussionmentioning

confidence: 99%

The Systemic Lupus Erythematosus Infection Predictive Index (LIPI): A Clinical-Immunological Tool to Predict Infections in Lupus Patients

et al. 2019

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Among autoimmune diseases, systemic lupus erythematosus (SLE) patients have a unique predisposition to develop infections, which represents one of their main causes of morbidity and mortality. Many infections occur at disease diagnosis in the absence of immunosuppressive therapy, suggesting that the immunological abnormalities in SLE patients might be fundamental for the development of this complication. The aim of this study was to address the main clinical and immunological features associated with the development of infection and to create and validate a compound clinical-immunological infection predictive index in a cohort of SLE patients. We included 55 SLE patients with < 5 years since diagnosis. The clinical and immunological features were evaluated periodically and patients were followed-up during 1 year, searching for the development of infection. Immunophenotyping was performed by multiparametric flow cytometry and neutrophil extracellular traps (NETs) were assessed by confocal microscopy. Eighteen patients (32.7%) presented 19 infectious events, 5 (26.3%) were severe. For the construction of the index, we performed a logistic regression analysis and the cutoff points were determined with ROC curves. Increased numbers of peripheral Th17 cells, B cell lymphopenia, and lower TLR2 expression in monocytes, as well as the use of cyclophosphamide were the major risk factors for the development of infection and thus were included in the index. Besides, patients that developed infection were characterized by increased numbers of low-density granulocytes (LDGs) and higher expression of LL-37 in NETs upon infection. Finally, we validated the index retrospectively in a nested case-control study. A score >1.5 points was able to predict infection in the following year (AUC = 0.97; LR– = 0.001, specificity 100%, P = 0.0003). Our index encompasses novel immunological features able to prospectively predict the risk of infection in SLE patients.

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“…GILZ also inhibits the expression of the Toll like receptor 2 (TLR2), thus limiting the recognition of bacterial components and the associated inflammatory signaling (143). GCs however also enhance the expression of TLR2 in a cell-type specific manner (144, 145), suggesting that GILZ may act as a homeostatic brake on GC enhanced TLR2 signaling. Furthermore, GC-induced GILZ expression is strongly reduced in annexin A1 deficient macrophages, therefore preventing the downregulation of the pro-inflammatory cytokines IL-1, IL-6, and TNFα (146, 147).…”

Section: Glucocorticoids and Gene Expression In Macrophages—molecularmentioning

confidence: 99%

Glucocorticoids Shape Macrophage Phenotype for Tissue Repair

et al. 2019

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Inflammation is a complex process which is highly conserved among species. Inflammation occurs in response to injury, infection, and cancer, as an allostatic mechanism to return the tissue and to return the organism back to health and homeostasis. Excessive, or chronic inflammation is associated with numerous diseases, and thus strategies to combat run-away inflammation is required. Anti-inflammatory drugs were therefore developed to switch inflammation off. However, the inflammatory response may be beneficial for the organism, in particular in the case of sterile tissue injury. The inflammatory response can be divided into several parts. The first step is the mounting of the inflammatory reaction itself, characterized by the presence of pro-inflammatory cytokines, and the infiltration of immune cells into the injured area. The second step is the resolution phase, where immune cells move toward an anti-inflammatory phenotype and decrease the secretion of pro-inflammatory cytokines. The last stage of inflammation is the regeneration process, where the tissue is rebuilt. Innate immune cells are major actors in the inflammatory response, of which, macrophages play an important role. Macrophages are highly sensitive to a large number of environmental stimuli, and can adapt their phenotype and function on demand. This change in phenotype in response to the environment allow macrophages to be involved in all steps of inflammation, from the first mounting of the pro-inflammatory response to the post-damage tissue repair.

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Cell type-specific regulatory effects of glucocorticoids on cutaneous TLR2 expression and signalling

Cited by 8 publications

References 69 publications

Toll-Like Receptor 2 Release by Macrophages: An Anti-inflammatory Program Induced by Glucocorticoids and Lipopolysaccharide

Toll-Like Receptor 2 Release by Macrophages: An Anti-inflammatory Program Induced by Glucocorticoids and Lipopolysaccharide

The Systemic Lupus Erythematosus Infection Predictive Index (LIPI): A Clinical-Immunological Tool to Predict Infections in Lupus Patients

Glucocorticoids Shape Macrophage Phenotype for Tissue Repair

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