Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin α4

Li, Lushen; Shirkey, Marina W.; Piao, Wenji; Li, Xiaofei; Zhao, Jing; Mei, Zhongcheng; Guo, Yanxia; Saxena, Vikas; Kensiski, Allison; Gavzy, Samuel J.; Song, Yang; Ma, Bing; Wu, Jing; Xiong, Yanbao; Wu, Long; Fan, Xiaoxuan; Roussey, Holly; Li, Meng; Krupnick, Alexæander S; Abdi, Reza; Bromberg, Jonathan S.

doi:10.1172/jci156994

Cited by 18 publications

(21 citation statements)

References 75 publications

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“…The naive control mice received an isotype control antibody. Cell preparation and sequencing methods were described previously ( 135 ). The raw data have been deposited in the NCBI Gene Expression Omnibus database (GEO GSE213400 for anti-CD40L group; GSE202068 for control group) ( 135 ).…”

Section: Methodsmentioning

confidence: 99%

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Zhao¹,

Jung²,

Li³

et al. 2022

Journal of Clinical Investigation

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The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1 + FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79–anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79–anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.

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Section: Methodsmentioning

confidence: 99%

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Zhao¹,

Jung²,

Li³

et al. 2022

Journal of Clinical Investigation

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“…Li et al. noted that PDGFRB is exclusively expressed in Lymph node fibroblastic reticular cells (FRCs) and depleting FRC-ECM (extracellular matrix) laminin α4 causes reduction in Tregs and dendritic cells ( 86 ). Additionally, a recent study suggested that BCR signaling pathway may be involved in PD with Down syndrome ( 87 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of a classifier based on hub aging-related genes and aging subtypes correlation with immune microenvironment for periodontitis

et al. 2022

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BackgroundPeriodontitis (PD), an age-related disease, is characterized by inflammatory periodontal tissue loss, and with the general aging of the global population, the burden of PD is becoming a major health concern. Nevertheless, the mechanism underlying this phenomenon remains indistinct. We aimed to develop a classification model for PD and explore the relationship between aging subtypes and the immune microenvironment for PD based on bioinformatics analysis.Materials and MethodsThe PD-related datasets were acquired from the Gene Expression Omnibus (GEO) database, and aging-related genes (ARGs) were obtained from the Human Aging Genomic Resources (HAGR). Four machine learning algorithms were applied to screen out the hub ARGs. Then, an artificial neural network (ANN) model was constructed and the accuracy of the model was validated by receiver operating characteristic (ROC) curve analysis. The clinical effect of the model was evaluated by decision curve analysis (DCA). Consensus clustering was employed to determine the aging expression subtypes. A series of bioinformatics analyses were performed to explore the PD immune microenvironment and its subtypes. The hub aging-related modules were defined using weighted correlation network analysis (WGCNA).ResultsTwenty-seven differentially expressed ARGs were dysregulated and a classifier based on four hub ARGs (BLM, FOS, IGFBP3, and PDGFRB) was constructed to diagnose PD with excellent accuracy. Subsequently, the mRNA levels of the hub ARGs were validated by quantitative real-time PCR (qRT-PCR). Based on differentially expressed ARGs, two aging-related subtypes were identified. Distinct biological functions and immune characteristics including infiltrating immunocytes, immunological reaction gene sets, the human leukocyte antigen (HLA) gene, and immune checkpoints were revealed between the subtypes. Additionally, the black module correlated with subtype-1 was manifested as the hub aging-related module and its latent functions were identified.ConclusionOur findings highlight the critical implications of aging-related genes in modulating the immune microenvironment. Four hub ARGs (BLM, FOS, IGFBP3, and PDGFRB) formed a classification model, and accompanied findings revealed the essential role of aging in the immune microenvironment for PD, providing fresh inspiration for PD etiopathogenesis and potential immunotherapy.

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“…Moreover, though our transcriptomic and microscopic analyses revealed a decreased inflammatory burden in the eWAT of HFD-fed Lama4 AKO mice, we did not determine which immune cell populations are affected. Indeed, deletion of LAMA4 in fibroblastic reticular cells of the lymph node affects Treg and dendritic cell populations [ 31 ], so it will be important in the future to examine how immune cell populations are regulated by adipocyte LAMA4 deletion. Lastly, we performed our initial analyses on male mice only at a single age.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

et al. 2022

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Laminins are heterotrimeric glycoproteins with structural and functional roles in basement membranes. The predominant laminin alpha chain found in adipocyte basement membranes is laminin α4 (LAMA4). Global LAMA4 deletion in mice leads to reduced adiposity and increased energy expenditure, but also results in vascular defects that complicate the interpretation of metabolic data. Here, we describe the generation and initial phenotypic analysis of an adipocyte-specific LAMA4 knockout mouse (Lama4AKO). We first performed an in-silico analysis to determine the degree to which laminin α4 was expressed in human and murine adipocytes. Next, male Lama4AKO and control mice were fed chow or high-fat diets and glucose tolerance was assessed along with serum insulin and leptin levels. Adipocyte area was measured in both epididymal and inguinal white adipose tissue (eWAT and iWAT, respectively), and eWAT was used for RNA-sequencing. We found that laminin α4 was highly expressed in human and murine adipocytes. Further, chow-fed Lama4AKO mice are like control mice in terms of body weight, body composition, and glucose tolerance, although they have larger eWAT adipocytes and lower insulin levels. High-fat-fed Lama4AKO mice are fatter and more glucose tolerant when compared to control mice. Transcriptionally, the eWAT of high-fat fed Lama4AKO mice resembles that of chow-fed control mice. We conclude from these findings that adipocyte-specific LAMA4 deletion is protective in an obesogenic environment, even though overall adiposity is increased.

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Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin α4

Cited by 18 publications

References 75 publications

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Identification and validation of a classifier based on hub aging-related genes and aging subtypes correlation with immune microenvironment for periodontitis

Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

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