Antibody-mediated targeting of cleavage-specific OPN-T cell interactions

Wanko, Bettina; Tardelli, Matteo; Jürets, Alexander; Neuhofer, Angelika; Prager, Gerhard; Morser, John; Leung, Lawrence L.K.; Staffler, Günther; Zeyda, Maximilian; Stulnig, Thomas

doi:10.1371/journal.pone.0214938

Cited by 2 publications

(3 citation statements)

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“…This results in the recruitment of macrophages [ 332 ], T cells [ 334 ] and APCs expressing CD44 that acts as an osteopontin receptor [ 333 ]. Intriguingly, not only full-length osteopontin but also MMP-cleaved derivatives potentiate T cell viability [ 334 ]. Moreover, MMP-cleaved osteopontin blunts insulin sensitivity of adipocytes compared with full-length osteopontin [ 328 ].…”

Section: Chasing Adipose Selective Drug Deliverymentioning

confidence: 99%

“…Its levels increase in WAT upon HFD feeding and β3 adrenergic stimulation through secretion by macrophages [331][332][333]. This results in the recruitment of macrophages [332], T cells [334] and APCs expressing CD44 that acts as an osteopontin receptor [333]. Intriguingly, not only full-length osteopontin but also MMP-cleaved derivatives potentiate T cell viability [334].…”

Section: Proteolytic Cleavagementioning

confidence: 99%

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Identification and characterization of adipose surface epitopes

Onogi

Khalil

Ussar

2020

Biochemical Journal

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Adipose tissue is a central regulator of metabolism and an important pharmacological target to treat the metabolic consequences of obesity, such as insulin resistance and dyslipidemia. Among the various cellular compartments, the adipocyte cell surface is especially appealing as a drug target as it contains various proteins that when activated or inhibited promote adipocyte health, change its endocrine function and eventually maintain or restore whole-body insulin sensitivity. In addition, cell surface proteins are readily accessible by various drug classes. However, targeting individual cell surface proteins in adipocytes has been difficult due to important functions of these proteins outside adipose tissue, raising various safety concerns. Thus, one of the biggest challenges is the lack of adipose selective surface proteins and/or targeting reagents. Here, we discuss several receptor families with an important function in adipogenesis and mature adipocytes to highlight the complexity at the cell surface and illustrate the problems with identifying adipose selective proteins. We then discuss that, while no unique adipocyte surface protein might exist, how splicing, posttranslational modifications as well as protein/protein interactions can create enormous diversity at the cell surface that vastly expands the space of potentially unique epitopes and how these selective epitopes can be identified and targeted.

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Section: Chasing Adipose Selective Drug Deliverymentioning

confidence: 99%

Section: Proteolytic Cleavagementioning

confidence: 99%

Identification and characterization of adipose surface epitopes

Onogi

Khalil

Ussar

2020

Biochemical Journal

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“…However, SPP1 is also key regulator of T cells and it regulates the Th1 response [22,23]. Since only a correlation between SPP1 gene expression and T-cell markers in AT has been reported [24], we here investigated its potential role in these processes, focusing on T-cell recruitment and polarization in AT and liver in a mouse model of obesity and in Spp1-knockout (KO) mice. Its human relevance was also investigated in the context of obesity, T2D, and MAFLD, as well as after weight loss.…”

Section: Introductionmentioning

confidence: 99%

Osteopontin‐driven T‐cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD

Soysouvanh,

Rousseau,

Bonnafous

et al. 2023

Obesity

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ObjectiveThis study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T‐cell regulation in initiation of obesity‐driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic‐associated fatty liver disease (MAFLD) development.MethodsSPP1 and T‐cell marker expression was evaluated in AT and liver according to type 2 diabetes and MAFLD in human individuals with obesity. The role of SPP1 on T cells was evaluated in Spp1‐knockout mice challenged with a high‐fat diet.ResultsIn humans with obesity, elevated SPP1 expression in AT was parallel to T‐cell marker expression (CD4, CD8A) and IR. Weight loss reversed AT inflammation with decreased SPP1 and CD8A expression. In liver, elevated SPP1 expression correlated with MAFLD severity and hepatic T‐cell markers. In mice, although Spp1 deficiency did not impact obesity, it did improve AT IR associated with prevention of proinflammatory T‐cell accumulation at the expense of regulatory T cells. Spp1 deficiency also decreased ex vivo helper T cell, subtype 1 (Th1) polarization of AT CD4+ and CD8+ T cells. In addition, Spp1 deficiency significantly reduced obesity‐associated liver steatosis and inflammation.ConclusionsCurrent findings highlight a critical role of SPP1 in the initiation of obesity‐driven chronic inflammation by regulating accumulation and/or polarization of T cells. Early targeting of SPP1 could be beneficial for IR and MAFLD treatment.

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Antibody-mediated targeting of cleavage-specific OPN-T cell interactions

Cited by 2 publications

References 40 publications

Identification and characterization of adipose surface epitopes

Identification and characterization of adipose surface epitopes

Osteopontin‐driven T‐cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD

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