CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells

Henn, Volker; Slupsky, Joseph R.; Gräfe, Michael; Anagnostopoulos, Ioannis; Förster, Reinhold; Müller‐Berghaus, Gert; Kroczek, Richard A.

doi:10.1038/35393

Cited by 1,930 publications

(1,581 citation statements)

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“…Future experiments are aimed at elucidating the mechanisms by with anti-CD40L mAb promote “tolerogenic” neutrophils. In this respect we hypothesize neutrophils scanning for platelets (35) may receive a “tolerogenic” signal following CD40L blockade in activated platelets (36) that may lead to CSF1 production and transplantation tolerance under sterile inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

Braza

Conde

Garcia

et al. 2018

American Journal of Transplantation

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Summary The colony-stimulating factor 1 (CSF1) regulates the differentiation and function of tissue macrophages and determines the outcome of the immune response. The molecular mechanisms behind CSF1-mediated macrophage development remain to be elucidated. Here we demonstrate that neutrophil-derived CSF1 controls macrophage polarization and proliferation, which is necessary for the induction of tolerance. Inhibiting neutrophil production of CSF1 or preventing macrophage proliferation, using targeted nanoparticles loaded with the cell cycle inhibitor simvastatin, abrogates the induction of tolerance. These results provide new mechanistic insights into the developmental requirements of tolerogenic macrophages and identify CSF1 producing neutrophils as critical regulators of the immunological response.

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Section: Discussionmentioning

confidence: 99%

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

Braza

Conde

Garcia

et al. 2018

American Journal of Transplantation

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“…In the latter case, activated platelets expressing or releasing CD40L [22,24] could also interact with CD40 on duct cells, since islet cell suspensions are directly injected into the portal vein. CD40-CD40L interactions at the pancreatic duct cell level could therefore contribute to beta cell damage in Type 1 diabetes and after islet transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…The ligand for CD40 (CD40L) is a type II transmembrane protein expressed on stimulated T cells but also on mast cells, basophils and platelets. A soluble form of CD40L is released from activated platelets or shed from stimulated lymphocytes [21,22,23,24]. CD40-CD154 interactions were shown to play a pivotal role in different T-cell-mediated inflammatory disorders [20,21,25,26,27] and disruption of CD40-CD40L interactions proved to be sufficient to prevent the development and progression of several autoimmune diseases [28,29] as well as allograft rejection [21,26].…”

Section: Introductionmentioning

confidence: 99%

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

Vosters

Beuneu

Nagy³

et al. 2004

Diabetologia

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Aims/hypothesis. Human pancreatic duct cells are closely associated with islet beta cells, and contaminate islet suspensions transplanted in Type 1 diabetes mellitus patients. Activated duct cells produce cytotoxic mediators and possibly contribute to the pathogenesis of Type 1 diabetes mellitus or islet graft rejection. As CD40 transduces activation signals involved in inflammatory and immune disorders, we investigated CD40 expression on duct cells and their response to CD40 engagement. Methods. CD40 expression on human pancreatic duct cells was analysed by flow cytometry and immunohistochemical analyses. To assess the function of CD40 expression on duct cells, activation of the transcription factor nuclear factor-kappa B was determined using electrophoretic mobility shift assay and ELISA. Cytokine mRNA levels were quantified by real-time RT-PCR, and protein levels by Luminex technology. Results. Isolated human pancreatic duct cells and Capan-2 cell lines were found to express constitutively CD40. The expression of CD40 on duct cells was confirmed in vivo on human normal and pathological pancreatic specimens. CD40 ligation on Capan-2 cells induced rapid nuclear factor-kappa B activation, and supershift assays demonstrated that p50/p65 heterodimers and p50/p50 homodimers were present in the activated complexes in the nucleus. This activation was accompanied by tumour necrosis factor-α and interleukin-1β mRNA accumulation. Tumour necrosis factor-α protein secretion was confirmed in CD40-activated Capan-2 cells and in isolated human pancreatic duct cells. Conclusions/interpretation. Interaction between activated T lymphocytes expressing CD40 ligand and duct cells expressing CD40 may contribute to the immune responses involved in Type 1 diabetes mellitus and islet graft rejection. Interfering with CD40-mediated duct cell activation could alleviate beta cell damage of immune origin.

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“…A cellular cross-talk might be required to efficiently trigger IFN-α secretion by PMNs. Owing to their proinflammatory activity [18,19], platelets might be involved. Indeed, platelets activated by immune complexes were recently shown to potentiate IFN-α secretion by PDCs in SLE through a CD154-CD40 interaction [20].…”

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confidence: 99%

Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

Decker

2011

Arthritis Res Ther

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Interferon-α plays a crucial role in the pathogenesis of systemic lupus erythematosus. Nevertheless, the different human cell types producing this cytokine as well as the stimuli inducing its production have not been completely characterized. So far, a subpopulation of dendritic cells activated by immune complexes has been identified as major producers of interferon-α in patients with lupus. However, those cells represent a minor population and some studies have reported the secretion of interferon-α by other cells. On the other hand, more than 50% of blood leukocytes are neutrophils and their functions are still not fully understood. Recent data suggest that neutrophils, though usually not considered interferon-α-producing cells, may represent an unexpected source of this cytokine in response to some lupus stimuli.

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CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells

Cited by 1,930 publications

References 25 publications

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

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