Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity

Yoo, Sehoon; Kim, Mingyo; Kang, Min‐Cheol; Kong, Jin-Sun; Kim, Ki-Myo; Lee, Saseong; Hong, Bong-Ki; Jeong, Gi Heon; Lee, Jin‐Hee; Shin, Min‐Gyeong; Kim, Yeon‐Gu; Apicella, Ivana; Cicatiello, Valeria; Falco, Sandro De; Yoon, Chong‐Hyeon; Cho, Chul-Soo; Ryoo, Zae Young; Lee, Seung‐Hyo; Kim, Wan‐Uk

doi:10.1038/s41590-019-0456-4

Cited by 43 publications

(35 citation statements)

References 40 publications

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“…As shown in Table 1, PlGF concentrations in the SF (n = 54) were well correlated with WBC counts (r = 0.466 and p = 0.001) and % neutrophils in the SF, as well as with blood levels of ESR and CRP as markers for systemic inflammatory responses in RA. Levels of sFlt-1, an anti-angiogenic protein used as a control 23 , also had a positive relationship with inflammatory markers in the blood (r = 0.364 and p = 0.007 for ESR, r = 0.496 and p < 0.001 for CRP). However, VEGF and IL-6 levels in the SF failed to correlate with ESR and CRP, although they showed positive correlations with WBC counts and % neutrophils in the SF (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…VEGF, PlGF, sFlt-1, and IL-6 measurements VEGF, PlGF, and IL-6 concentrations, which are major proangiogenic factors primarily secreted from proliferating synoviocytes 10,21,27 , were measured from the SF and sera of both RA and OA patients using an enzyme-linked immunosorbent assay (ELISA) as described previously 23 . As a control, the levels of sFlt-1, an anti-angiogenic molecule produced by synoviocytes 23 , were also determined in the same samples by ELISA. The detection limit of ELISA was 10 pg/ml for VEGF, PlGF, IL-6, and sFlt-1.…”

Section: Study Population and Sf And Serum Samplingmentioning

confidence: 99%

“…PlGF also promotes proliferation, survival, migration, and invasion of RA synoviocytes 22 , suggesting its role in the formation of the invasive pannus. We have recently demonstrated that PlGF secreted from T H 17 cells not only increases angiogenesis but also shifts naive T cells toward T H 17 cell polarization, thereby critically contributing to RA pathogenesis 23 . Together, PlGF shows pleotropic actions for RA pathology possibly by inducing angiogenesis, synoviocyte proliferation, and T H 17 cell generation.…”

Section: Introductionmentioning

confidence: 99%

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Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis

et al. 2020

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Angiogenesis and synoviocyte hyperplasia, called 'pannus,' are pathologic hallmarks of rheumatoid arthritis (RA). To determine the clinical significance of angiogenic cytokines in RA, the levels of pro-angiogenic cytokines, including VEGF, placenta growth factor (PlGF), and IL-6, were measured in the synovial fluid (SF, n = 54) and sera of RA patients (n = 157) using ELISA. Patients (n = 103) with disease activity score 28 (DAS28) > 3.2, which indicates moderate to high RA activity, underwent follow-up blood sampling at 6 months after treatment with conventional disease-modifying anti-rheumatic drugs (c-DMARD) or biologic DMARD (b-DMARD) including an anti-TNFα antibody, an anti-IL-6 antibody, and abatacept. Ultrasonography (US) was performed on affected joints to define the synovitis severity at the time of sampling. Consequently, in the SF of RA patients, PlGF and IL-6 levels correlated well with synovitis severity determined by US. In RA sera, VEGF and IL-6 levels were elevated in proportion to synovitis severity, correlating with conventional markers for disease activity, including ESR, CRP, and DAS28. In c-DMARD users (n = 53), serially monitored levels of serum VEGF, IL-6, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) all decreased in good and moderate responders but not in nonresponders. In b-DMARD users (n = 49), only serum VEGF well represented the treatment response, while CRP nonspecifically decreased irrespective of the treatment outcome. By multivariable analysis, serum ΔVEGF, but not ΔESR or ΔCRP, was an independent factor associated with good and moderate responses to DMARD. In summary, the angiogenic cytokines PlGF and VEGF represent the synovitis severity of RA assessed by US. In patients receiving b-DMARD, serum VEGF may be more valuable than CRP in reflecting the treatment response.

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Section: Resultsmentioning

confidence: 95%

Section: Study Population and Sf And Serum Samplingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis

et al. 2020

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“…Interestingly, some recent studies suggest previously unknown functions of STAT3 in tumor immunity. For instance, placental growth factor (PlGF) [ 65 ] and Cxxc finger protein 1 (Cxxc1) [ 66 ] can act as key upstream regulators of STAT3 signaling, which subsequently contributes to the differentiation and function of Th17 cells. STAT3 mediates the major impact of β2 adrenergic receptor on the immunosuppressive potential of myeloid-derived suppressor cells (MDSCs) in the TME [ 67 ].…”

Section: Stat3-driven Tumor Immunosuppressionmentioning

confidence: 99%

Targeting STAT3 in Cancer Immunotherapy

et al. 2020

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As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.

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“…Although the detailed mechanism behind their dichotomous nature is still unclear, it may have something to do with Th17 cell plasticity being influenced by the environment. Indeed, several environmental factors, such as sodium chloride [134], microbiota [135][136][137], and angiogenesis [138], may regulate the generation of pathogenic Th17 cells. In terms of cell plasticity, Th17 cells were reported to be unstable both in vitro and in vivo, and they may become Th1-like cells [53,139].…”

Section: Cd4 T Cell Plasticitymentioning

confidence: 99%

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

Zhu

2020

IJMS

224

138

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The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.

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Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity

Cited by 43 publications

References 40 publications

Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis

Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis

Targeting STAT3 in Cancer Immunotherapy

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

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