CXCL4 Exposure Potentiates TLR-Driven Polarization of Human Monocyte-Derived Dendritic Cells and Increases Stimulation of T Cells

Silva-Cardoso, Sandra; Affandi, Alsya J.; Spel, Lotte; Cossu, Marta; Roon, Joël A G van; Boes, Marianne

doi:10.4049/jimmunol.1602020

Cited by 41 publications

(52 citation statements)

References 78 publications

(91 reference statements)

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“…Several pathways involved in inflammatory responses 123 such as TLR signaling, interferon signaling, and cytokine signaling, were significantly 124 upregulated in CXCL4-moDCs compared to conventional moDCs (Figure 1-figure 125 supplement 2E). Confirming our previous findings (Silva-Cardoso et al, 2017), these 126 transcriptional changes were followed by increased production of pro-inflammatory mediators 127 such as IL-1β, IL-6, IL-12, IL-23, IL-27, TNF and CCL22, and down-regulation of immune-128 suppressive mediator CCL18 (validated using Luminex assays; see Figure 1J-K and Figure 1-129 figure supplement 2A-D). Pathways involved in cellular adhesion, integrin signaling, ECM 130 organization, and collagen formation, among others, were upregulated in CXCL4-moDCs upon 131 polyI:C stimulation compared to stimulated moDCs (Figure 1-figure supplement 2E), 132 indicating that CXCL4 exposure induces a pro-inflammatory and pro-fibrotic phenotype.…”

supporting

confidence: 82%

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of monocyte-derived cells

Tao

Angiolilli

et al. 2019

Preprint

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21Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete 22 understanding of the molecular mechanisms underlying fibrosis has severely hampered effective 23 drug development. CXCL4 is associated with the onset and extent of fibrosis development in 24 systemic sclerosis, a prototypic inflammatory and fibrotic disease. Here, we integrated 65 paired 25 longitudinal transcriptional and methylation profiles from monocyte-derived cells with/without 26 2 CXCL4 exposure. Using data-driven gene regulatory network analyses, we demonstrate that 27 CXCL4 dramatically alters the trajectory of monocyte differentiation, inducing a novel pro-28 inflammatory and pro-fibrotic phenotype mediated via key transcriptional regulators including 29 CIITA. CXCL4 exposed monocyte-derived cells directly trigger a fibrotic cascade by producing 30 ECM molecules and inducing myofibroblast differentiation. Inhibition of CIITA mimicked 31 CXCL4 in inducing a pro-inflammatory and pro-fibrotic phenotype, validating the relevance of 32 the gene regulatory network. Our study unveils CXCL4 as a key secreted factor driving innate 33 immune training and forming the long-sought link between inflammation and fibrosis. 34 35 106 antigen processing and presentation (Figure 1-figure supplement 1E). For instance, CXCL4-107 moDCs, in the absence of further stimulation, up-regulate expression of several inflammatory 108 molecules such as CTSL, FLT1, CD86, LAMP1, CHI3L1, and down-regulate signaling receptors 109 such as CLEC10A, IL1R1, IL1R2 compared to moDCs (Figure 1G-I and Figure 1-figure 110 supplement 1A-D). Strikingly, CXCL4 exposure also leads to dramatic changes in expression of 111 genes regulating metabolism and transcription (Figure 1-figure supplement 1E), reminiscent 112 of changes previously observed in myeloid cells undergoing immune training (Saeed et al., 2014). 113 Thus, CXCL4 orchestrates a differentiation process dramatically different than that of the 114 conventional moDCs. 115 116 Mature CXCL4-moDCs are functionally distinct from conventional moDCs 117 5To study the effects of CXCL4 on moDC maturation, we stimulated the cells with polyI:C on 118 day 7. This perturbed the expression of 8,949 and 7,767 genes in CXCL4-moDCs and 119 conventional moDCs, respectively, compared to the day 7 transcriptional profiles of their 120 unstimulated counterparts (Figure 1C and 1E, left and middle panels). 2,397 genes responded 121 differently to polyI:C stimulation in CXCL4-moDCs compared to conventional moDCs ( Figure 122 1C and Figure 1-figure supplement 2). Several pathways involved in inflammatory responses 123 such as TLR signaling, interferon signaling, and cytokine signaling, were significantly 124 upregulated in CXCL4-moDCs compared to conventional moDCs (Figure 1-figure 125 supplement 2E). Confirming our previous findings (Silva-Cardoso et al., 2017), these 126 transcriptional changes were followed by increased production of pro-inflammatory mediators 127 such as IL-1β, IL-6, IL-12, IL-23, IL-27, TNF and...

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supporting

confidence: 82%

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of monocyte-derived cells

Tao

Angiolilli

et al. 2019

Preprint

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“…3B), but not with pDCs or B cells. Previous data from others and our group indicate clear immunomodulatory effects of CXCL4 at higher doses [21,22]. In co-culture with monocytes, increasing amount of CXCL4 up to 5 μg/mL did not additionally enhance the IL-17 induction (Supporting Information Fig.…”

Section: Cxcl4 Induces Il-17 Production By Cd4 + T Cells When Co-cultmentioning

confidence: 57%

“…Previous works have shown that during monocyte differentiation into dendritic cell or macrophage, the addition of CXCL4 resulted in an altered expression of cell surface markers and a distinct transcriptomic profile . They also differed in their capacity to activate T cells, yet the effect on IL‐17 production was not assessed.…”

Section: Resultsmentioning

confidence: 99%

“…While there is little known about the effect of CXCL4 on mDC, we previously showed that CXCL4 could enhance IFN‐α production by pDCs upon toll‐like receptor stimulation . We recently demonstrated that CXCL4 potentiated moDCs cytokine production upon toll‐like receptor stimulation . Through regulating APC function, CXCL4 can promote an inflammatory environment that results in an increased IL‐17 production by CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

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CXCL4 is a novel inducer of human Th17 cells and correlates with IL‐17 and IL‐22 in psoriatic arthritis

et al. 2018

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CXCL4 regulates multiple facets of the immune response and is highly upregulated in various Th17‐associated rheumatic diseases. However, whether CXCL4 plays a direct role in the induction of IL‐17 production by human CD4+ T cells is currently unclear. Here, we demonstrated that CXCL4 induced human CD4+ T cells to secrete IL‐17 that co‐expressed IFN‐γ and IL‐22, and differentiated naïve CD4+ T cells to become Th17‐cytokine producing cells. In a co‐culture system of human CD4+ T cells with monocytes or myeloid dendritic cells, CXCL4 induced IL‐17 production upon triggering by superantigen. Moreover, when monocyte‐derived dendritic cells were differentiated in the presence of CXCL4, they orchestrated increased levels of IL‐17, IFN‐γ, and proliferation by CD4+ T cells. Furthermore, the CXCL4 levels in synovial fluid from psoriatic arthritis patients strongly correlated with IL‐17 and IL‐22 levels. A similar response to CXCL4 of enhanced IL‐17 production by CD4+ T cells was also observed in patients with psoriatic arthritis. Altogether, we demonstrate that CXCL4 boosts pro‐inflammatory cytokine production especially IL‐17 by human CD4+ T cells, either by acting directly or indirectly via myeloid antigen presenting cells, implicating a role for CXCL4 in PsA pathology.

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“…Methods: We differentiated human moDCs in the presence of CXCL4. After 6 days differentiation, cells were stimulated with a TLR3 ligand (polyI:C) as described in our previous study 2. RNA sequencing and DNA methylation profiling was performed at various time points during differentiation and stimulation.…”

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confidence: 99%

SAT0040 Safety, tolerability, pharmacokinetics and pharmacodynamics of bcd-089, novel monoclonal anti-il-6 receptor antibody: results from the first-in-human single dose escalation study in healthy volunteers

Khlyabova

Eremeeva

Lutckii

et al. 2018

Saturday, 16 JUNE 2018

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BackgroundBCD-089 is a fully human monoclonal antibody targeting membrane-bound and soluble forms of IL-6Rα, thereby blocking of IL-6 classic and trans- signalling. IL-6, a proinflammatory cytokine, plays a central role in the pathogenesis of many chronic inflammatory and autoimmune diseases. Thereby inhibition of IL-6 signalling is a promising approach in the treatment of immune-mediated pathology.ObjectivesTo assess safety, immunogenicity, pharmacokinetics and pharmacodynamics of a single administration of BCD-089.MethodsThis was a phase I, open label, single ascending dose clinical study in healthy male volunteers, aged 22–37 years (n=19). In 1 st cohort, one «sentinel» volunteer received 0.006 mg/kg of BCD-089. Volunteers in cohorts 2–7 received single doses of BCD-089 0.3, 0.625, 1.0, 1.6, 2.2 and 2.9 mg/kg, respectively. Every next cohort was included after completed safety evaluation for the previous one. Safety, PK/PD and immunogenicity were assessed during 71 days follow up.ResultsAll enrolled subjects have completed follow up period of 71 days. No withdrawals occurred. Single SC administration of BCD-089 was well tolerated and showed good safety profile at all tested doses: no grade 3/4 AEs, SAEs, DLTs or allergic reactions were reported in any cohort. None of the volunteers developed ADA to BCD-089. The only AEs reported were grade 1 or 2 laboratory abnormalities.Abstract SAT0040 – Table 1Subjects with abnormal test results, n (%). Table shows only cohorts where at least one abnormal test result was reported.Adverse events0.3 mg/kg(n=3)0.625 mg/kg(n=3)1.0 mg/kg (n=3)2.2 mg/kg(n=3)2.9 mg/kg (n=3) Grade 1 WBC decrease--1 (33.3%)2 (66.6%)1 (33.3%)Grade 1 neutropenia--1 (33.3%)1 (33.3%)-Grade 2 neutropenia---1 (33.3%)1 (33.3%)Grade 2 t.bilirubin increase-1 (33.3%)---Grade 1 AST decrease1 (33.3%)----Grade 1 Creatinine decrease-1 (33.3%)---Single SC administration of BCD-089 had a dose-dependent PK: the drug became detectable in the serum within the first 12 hour after injection for all tested doses (2–8 hour for doses>1.0 mg/kg). Serum concentration dose-proportionally increased and reached maximum at day 3 after administration, then gradually decreased. Elimination half-life showed significant inter-personal variability and dose-dependency, reflecting non-linear PK typical for drugs with target-mediated disposition.Abstract SAT0040 – Figure 1BCD-089(A), sIL6R(B), IL6(C) and CRP(D) serum concentration (Median and IQR).The concentration of soluble IL-6 receptor increased after BCD-089 administration in a dose-dependent manner. A raise in the concentration of IL-6 was seen at doses>1.0 mg/kg. Membrane IL-6R saturation of 90%>100% was seen at doses≥0.6 mg/kg. Regardless to the dose, serum CRP decreased below the limit of detection in most volunteers within the first week after injection. All tested PD markers returned to baseline at the end of the follow-up.ConclusionsSingle SC administration of BCD-089 was well tolerated, showed favourable safety profile and low immunogenicity at all tested doses in healthy vo...

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CXCL4 Exposure Potentiates TLR-Driven Polarization of Human Monocyte-Derived Dendritic Cells and Increases Stimulation of T Cells

Cited by 41 publications

References 78 publications

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of monocyte-derived cells

CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of monocyte-derived cells

CXCL4 is a novel inducer of human Th17 cells and correlates with IL‐17 and IL‐22 in psoriatic arthritis

SAT0040 Safety, tolerability, pharmacokinetics and pharmacodynamics of bcd-089, novel monoclonal anti-il-6 receptor antibody: results from the first-in-human single dose escalation study in healthy volunteers

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