Antibodies against nephronectin ameliorate anti‐type II collagen‐induced arthritis in mice

Kawa, Shigeyuki; Honda, Machiko; Ishikawa, Kiyoshi; Segawa, Tatsuya

doi:10.1002/2211-5463.12758

Cited by 4 publications

(4 citation statements)

References 30 publications

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“…It is known as a functional ligand of integrin α8/β-1 in kidney development and is also associated with the development, remodeling and survival of various tissues through the binding of integrins 52 , 53 . NPNT has also been implicated in inflammation and autoimmunity 54 , 55 , which may align with the suggested role of obesity-induced inflammation in COVID-19 severity 56 . In addition, NPNT is expressed in lung alveolar cells and fibroblasts 57 , 58 and recent GWASs have identified the same NPNT splice variant, rs34712979 , to be associated with lung function-related traits (for example, FEV 1 , FVC and FEV 1 /FVC ratio) and COPD 44 , 45 .…”

Section: Discussionsupporting

confidence: 61%

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

Yoshiji

Butler‐Laporte

et al. 2023

Nat Metab

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Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10 -10 ). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.

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Section: Discussionsupporting

confidence: 61%

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

Yoshiji

Butler‐Laporte

et al. 2023

Nat Metab

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“…It is known as a functional ligand of integrin α8/β-1 in kidney development and also associated with the development, remodeling, and survival of various tissues through the binding of integrins 43,44 . NPNT has also been implicated in inflammation and autoimmunity 45,46 , which may align with the suggested role of obesity-induced inflammation in COVID-19 severity 47 . In addition, NPNT is expressed in lung alveolar cells and fibroblasts 48,49 , and recent GWASs have identified that the same NPNT splice variant, rs34712979, is associated with lung function-related traits (e.g., forced expiratory volume (FEV1), forced vital capacity (FVC), FEV1/FVC) and COPD 39,40 .…”

Section: Discussionsupporting

confidence: 61%

“…It is known as a functional ligand of integrin α8/β-1 in kidney development and is also associated with the development, remodeling, and survival of various tissues through the binding of integrins 52,53 . NPNT has also been implicated in inflammation and autoimmunity 54,55 , which may align with the suggested role of obesity-induced inflammation in COVID-19 severity 56 .…”

Section: Discussionsupporting

confidence: 61%

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

Yoshiji

Butler‐Laporte

et al. 2022

Preprint

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Obesity is a major risk factor for COVID-19 severity; however, the underlying mechanism is not fully understood. Considering that obesity influences the human plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity. We first screened 4,907 plasma proteins to identify proteins influenced by body mass index (BMI) using Mendelian randomization (MR). This yielded 1,216 proteins, whose effects on COVID-19 severity were assessed, again using MR. This two-step approach identified nephronectin (NPNT), for which a one standard deviation increase was associated with severe COVID-19 (odds ratio = 1.71, 95% CI: 1.45–2.02, P = 1.63 × 10-10). Colocalization analyses indicated that an NPNT splice isoform drove this effect. Overall, NPNT mediates 3.7% of the total effect of BMI on severe COVID-19. Finally, we found that decreasing body fat mass and increasing fat-free mass can lower NPNT levels and thus may improve COVID-19 outcomes. These findings provide actionable insights into how obesity influences COVID-19 severity.

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“…Furthermore, by mutating the integrin-binding motifs, metastasis of breast cancer cells was significantly reduced [ 12 , 34 ]. Through antibody blocking of the RGD and LFEIFEIER sequence, collagen-induced inflammatory arthritis was reduced [ 35 ]. The RGD and partially the LFEIFEIER sequence have also been suggested to be involved in recruitment of CD4+ T cells in both acute and chronic liver hepatitis [ 36 ].…”

Section: Npnt Structure and Domain Related Functionsmentioning

confidence: 99%

Nephronectin as a Matrix Effector in Cancer

Magnussen

Toraskar

Hadler‐Olsen

et al. 2021

Cancers

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The extracellular matrix protein nephronectin plays an important regulatory role during embryonic development, controlling renal organogenesis through integrin α8β1 association. Nephronectin has three main domains: five N-terminal epidermal growth factor-like domains, a linker region harbouring two integrin-binding motifs (RGD and LFEIFEIER), and a C-terminal MAM domain. In this review, we look into the domain-related functions of nephronectin, and tissue distribution and expression. During the last two decades it has become evident that nephronectin also plays a role during cancer progression and in particular metastasis. Nephronectin is overexpressed in both human and mouse breast cancer compared to normal breast tissue where the protein is absent. Cancer cells expressing elevated levels of nephronectin acquire increased ability to colonise distant organs. In particular, the enhancer-motif (LFEIFEIER) which is specific to the integrin α8β1 association induces viability via p38 MAPK and plays a role in colonization. Integrins have long been desired as therapeutic targets, where low efficiency and receptor redundancy have been major issues. Based on the summarised publications, the enhancer-motif of nephronectin could present a novel therapeutic target.

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Antibodies against nephronectin ameliorate anti‐type II collagen‐induced arthritis in mice

Cited by 4 publications

References 30 publications

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

Nephronectin as a Matrix Effector in Cancer

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