GDF15 Regulates Malat-1 Circular RNA and Inactivates NFκB Signaling Leading to Immune Tolerogenic DCs for Preventing Alloimmune Rejection in Heart Transplantation

Zhang, Yixin; Zhang, Guangfeng; Liu, Yanling; Chen, Renqi; Zhao, Danyang; McAlister, Vivian C.; Mele, Tina; Liu, Kexiang; Zheng, Xiufen

doi:10.3389/fimmu.2018.02407

Cited by 68 publications

(69 citation statements)

References 46 publications

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“…Inhibition of LFA-1 by GDF-15 would also impair the priming of antigen-specific T cells by dendritic cells. Such functional outcomes were independently observed in other studies (99,175). The latter study also found that a knockout of GDF-15 in immature dendritic cells promotes their maturation and enhances their immune stimulatory potential.…”

Section: Signaling Of Gdf-15 In the Tumor Microenvironmentsupporting

confidence: 74%

“…Transgenic expression of GDF-15 in dendritic cells, in contrast, induces immune-inhibitory molecules in dendritic cells which then enhance T cell exhaustion and promote the generation of regulatory T cells. Mechanistically, the observed GDF-15 mediated induction of a tolerogenic dendritic cell phenotype was found to depend on TGF-β receptors I and II (rather than on GFRAL), on repression of malate-1 circular RNA expression, on inhibition of NF-κB signaling, and on the induction of indoleamine-2,3-dioxygenase (IDO1) in dendritic cells (175). Effects of GDF-15 on LFA-1 were not investigated and possible problems resulting from the use of recombinant human GDF-15 (which may have contained TGF-β) were not discussed.…”

Section: Signaling Of Gdf-15 In the Tumor Microenvironmentmentioning

confidence: 98%

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Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

2020

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Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is welldocumented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.

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Section: Signaling Of Gdf-15 In the Tumor Microenvironmentsupporting

confidence: 74%

Section: Signaling Of Gdf-15 In the Tumor Microenvironmentmentioning

confidence: 98%

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

2020

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“…Besides the contribution of cholinergic receptors, we supposed the contribution of neurotrophic factors, axon-guidance proteins, and their respective receptors in neuron-MΦ interactions. GDF15 has been reported to suppress inflammatory responses in a murine model of endotoxin-induced sepsis and prevent maturation of inflammatory dendritic cells in a heart-transplantation model 91, 92 . Using an imiquimod- or IL-23-induced mouse model of psoriasis-like skin inflammation, GDF11 administration attenuated the severity of skin inflammation via suppression of the NF-κB signaling pathway 93 .…”

Section: Discussionmentioning

confidence: 99%

Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung’s disease

Keck

Galati-Fournier

Kym

et al. 2020

Preprint

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Background & AimsHirschsprung’s disease (HSCR) is a congenital intestinal motility disorder defined by the absence of enteric nervous cells (ganglia). The development of HSCR-associated enterocolitis remains a life-threatening complication. Absence of enteric ganglia implicates extramural innervation of acetylcholine-secreting (cholinergic) nerve fibers. Cholinergic signals have been reported to control excessive inflammation, but the impact on HSCR-associated enterocolitis is unknown.MethodsWe enrolled 44 HSCR patients in a prospective multicenter study and grouped them according to their degree of colonic mucosal cholinergic innervation using immunohistochemistry. The fiber phenotype was correlated with the tissue cytokine profile as well as immune cell frequencies using quantitative reverse-transcribed real-time polymerase chain reaction (qRT-PCR) of whole colonic tissue and fluorescence-activated cell sorting (FACS) analysis of isolated colonic immune cells. Fiber-associated immune cells were identified using confocal immunofluorescence microscopy and characterized by RNA-seq analysis. Microbial dysbiosis was analyzed in colonic patient tissue using 16S rDNA gene sequencing. Finally, the fiber phenotype was correlated with postoperative enterocolitis manifestation.ResultsWe provided evidence that extrinsic mucosal innervation correlated with reduced interleukin (IL)-17 cytokine levels and T-helper-17 (Th17) cell frequencies. Bipolar CD14high macrophages colocalized with neurons and expressed significantly less interleukin-23, a Th17-promoting cytokine. HSCR patients lacking mucosal cholinergic nerve fibers showed microbial dysbiosis and had a higher incidence of postoperative enterocolitis.ConclusionThe mucosal fiber phenotype might serve as a new prognostic marker for enterocolitis development in HSCR patients and may offer an approach to personalized patient care and new future therapeutic options. (www.clinicaltrials.gov accessing number NCT03617640)

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“…The high expression of IL-27 is also correlated with the induction of IL-10 expressing CD4 + T cells ( 106 ). Moreover, DC transfected with MIC expression adenovirus could enhance T cell exhaustion and Treg proliferation and consequently promote the survival of cardiac allograft ( 100 , 107 ).…”

Section: The Function Of Tol-dcmentioning

confidence: 99%

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

et al. 2020

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Over a half century, organ transplantation has become an effective method for the treatment of end-stage visceral diseases. Although the application of immunosuppressants (IS) minimizes the rate of allograft rejection, the common use of IS bring many adverse effects to transplant patients. Moreover, true transplant tolerance is very rare in clinical practice. Dendritic cells (DCs) are thought to be the most potent antigen-presenting cells, which makes a bridge between innate and adaptive immunity. Among their subsets, a small portion of DCs with immunoregulatory function was known as tolerogenic DC (Tol-DC). Previous reports demonstrated the ability of adoptively transferred Tol-DC to approach transplant tolerance in animal models. In this study, we summarized the properties, ex vivo generation, metabolism, and clinical attempts of Tol-DC. Tol-DC is expected to become a substitute for IS to enable patients to achieve immune tolerance in the future.

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GDF15 Regulates Malat-1 Circular RNA and Inactivates NFκB Signaling Leading to Immune Tolerogenic DCs for Preventing Alloimmune Rejection in Heart Transplantation

Cited by 68 publications

References 46 publications

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung’s disease

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

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