P107 Interferon-induced metabolic perturbations shape the inflammatory status of human monocytes: implications for innovative therapeutic engineering in SLE autoimmunity (original) (raw)
Related papers
Veterinary Immunology and Immunopathology, 2008
The immune stimulatory effects of synthetic CpG DNA, on porcine peripheral blood mononuclear cells (PBMC) have been reported, but little is known about CpG-induced responses in other lymphoid tissues of pigs. We investigated innate immune responses induced by CpG DNA in cells from blood, lymph nodes (LN) and spleens of pigs. Porcine PBMC and lymph node cells (LNC) were stimulated in vitro with three classes (A-, B-and C-class) of CpG oligodeoxynucleotides (ODNs), and a non-CpG control ODN. All three classes of CpG ODNs induced significant production of IFNa, TNFa, IL-1, IL-6 and IL-12 in PBMC. In contrast, in LNC, only IL-12 was stimulated by all three classes of CpG ODNs, while IFNa, and IL-6 were induced by A-and Cclass ODNs. No TNFa was induced in LNC by any of the ODNs. Significant lymphocyte proliferation was induced in PBMC by all three classes of CpG ODNs and non-CpG control. However, in LNC, B-and C-class ODNs induced significant proliferation, while no proliferation was seen with A-class and non-CpG control ODN. All three classes of ODNs induced NK-like cytotoxicity in PBMC and spleen cells, but were less effective in inducing NK cytotoxicity in LNC. We then investigated the reasons for the relatively poor CpG-induced responses in LNC. Our investigations revealed that LNC had a lower frequency of IFNa-secreting cells and expressed low levels of TLR9 mRNA compared to PBMC. We conclude that the lower number of IFNa-secreting cells and receptor expression may contribute to the attenuated responses in LNC following stimulation with CpG ODN. #
The Journal of Immunology, 2002
IFN-is a recently identified type I IFN that exhibits both structural and functional homology with the other type I IFN subclasses. In this study, we have investigated the effect of IFN-on cells of the innate immune system by comparing cytokine release following treatment of human cells with either IFN-or two recombinant IFN subtypes, IFN- and IFN-␣2a. Although IFN-␣2a failed to stimulate monocyte cytokine secretion, IFN-, like IFN-, induced the release of several cytokines from both monocytes and dendritic cells, without the requirement of a costimulatory signal. IFN-was particularly effective in inhibiting inducible IL-12 release from monocytes. Unlike IFN-, IFN-did not induce release of IFN-␥ by PBL. Expression of the IFN-mRNA was observed in resting dendritic cells and monocytes, and it was up-regulated by IFN-␥ stimulation in monocytes, while IFN- mRNA was minimally detectable under the same conditions. Monocyte and dendritic cell expression of IFN-was also confirmed in vivo in chronic lesions of psoriasis vulgaris and atopic dermatitis. Finally, biosensor-based binding kinetic analysis revealed that IFN-, like IFN-, binds strongly to heparin (K d : 2.1 nM), suggesting that the cytokine can be retained close to the local site of production. The pattern of cytokines induced by IFN-in monocytes, coupled with the unique induction of IFN-mRNA by IFN-␥, indicates a potential role for IFN-in the regulation of immune cell functions.
Induction of CD83+CD14+ Nondendritic Antigen-Presenting Cells by Exposure of Monocytes to IFN-
The Journal of Immunology, 2008
IFN-␣ is a well-known agent for treatment of viral and malignant diseases. It has several modes of actions, including direct influence on the immune system. We investigated IFN-␣ effects on PBMC in terms of dendritic cell (DC) differentiation, as PBMC are exposed to high IFN-␣ levels during treatment of infections and cancers. We show that in vitro IFN-␣ exposure induced rapid and strong up-regulation of the DC-maturation markers CD80, CD86, and CD83 in bulk PBMC. Consistently, IFN-␣ induced up-regulation of these molecules on purified monocytes within 24 h. Up-regulation of CD80 and CD83 expression was IFN-␣ concentration-dependent. In contrast to GM-CSF ؉ IL-4-generated DCs, most of the IFN-␣-challenged CD83 ؉ cells coexpressed the monocyte marker CD14. Despite a typical mature DC immunophenotype, IFN-␣-treated monocytes conserved phagocytic activity and never acquired a dendritic morphology. In mixed lymphocyte reactions IFN-␣-treated monocytes were less potent than GM-CSF ؉ IL-4-generated DCs but significantly more potent than untreated monocytes to induce T cell proliferation in bulk PBMC. However, only GM-CSF ؉ IL-4-generated DCs were able to induce a significant proliferation of naive CD4 ؉ T cells. Notably, autologous memory CD4 ؉ T cells proliferated when exposed to tetanus toxoid-pulsed IFN-␣-treated monocytes. At variance with untreated or GM-CSF ؉ IL-4-exposed monocytes, those challenged with IFN-␣ showed long-lasting STAT-1 phosphorylation. Remarkably, CD83 ؉ CD14 ؉ cells were present in varicella skin lesions in close contact with IFN-␣-producing cells. The present findings suggest that IFN-␣ alone promptly generates nondendritic APCs able to stimulate memory immune responses. This may represent an additional mode of action of IFN-␣ in vivo.
Critical Role of the Endogenous IFN Ligand-Receptors in Type I and Type II IFNs Response
Immunology, 2014
Separate ligand-receptor paradigms are commonly used for each type of interferon (IFN). However, accumulating evidence suggests that type I and type II IFNs may not be restricted to independent pathways. Using different cell types deficient in IFNAR1, IFNAR2, IFNGR1, IFNGR2 and IFN-c, we evaluated the contribution of each element of the IFN system to the activity of type I and type II IFNs. We show that deficiency in IFNAR1 or IFNAR2 is associated with impairment of type II IFN activity. This impairment, presumably resulting from the disruption of the ligandreceptor complex, is obtained in all cell types tested. However, deficiency of IFNGR1, IFNGR2 or IFN-c was associated with an impairment of type I IFN activity in spleen cells only, correlating with the constitutive expression of type II IFN (IFN-c) observed on those cells. Therefore, in vitro the constitutive expression of both the receptors and the ligands of type I or type II IFN is critical for the enhancement of the IFN activity. Any IFN deficiency can totally or partially impair IFN activity, suggesting the importance of type I and type II IFN interactions. Taken together, our results suggest that type I and type II IFNs may regulate biological activities through distinct as well as common IFN receptor complexes.
TLR Agonists That Induce IFN- Abrogate Resident Macrophage Suppression of T Cells
The Journal of Immunology, 2010
185:4545-4553; Prepublished online 15 J Immunol Material Supplementary 5.DC1.html http://www.jimmunol.org/content/suppl/2010/09/16/jimmunol.100204 References http://www.jimmunol.org/content/185/8/4545.full#ref-list-1 , 24 of which you can access for free at: cites 44 articles This article Subscriptions http://jimmunol.org/subscriptions is online at: The Journal of Immunology Information about subscribing to
Arthritis Research & Therapy, 2020
Objective: Patients with systemic lupus erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III IFN in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1-associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC-stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6, or granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p < 0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.