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Inhibition of Fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development.

ABSTRACT: Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of pancreatic insulin-producing ? cells by autoreactive T cells early in life. Despite daily insulin injections, patients typically develop cardiovascular and other complications; and intensive efforts are being directed toward identifying therapeutic targets to prevent the disease without directly impinging on the host defense. Fas ligand (FasL) is one potential target. Fas-FasL interactions primarily regulate T-cell homeostasis, not activation. Nevertheless, spontaneous gene mutation of Fas (called lpr mutation) or FasL (called the gld mutation) prevents autoimmune diabetes in nonobese diabetic (NOD) mice, the widely used model for T1D. Furthermore, although homozygous gld mutations cause age-dependent lymphoproliferation, limiting the gld mutation to one allele (NOD-gld/+) or treating NOD-wild-type mice with FasL-neutralizing monoclonal antibody completely prevents the disease development without causing lymphoproliferation or immune suppression. Herein, we show that the heterozygous gld mutation inhibits the accumulation of diabetogenic T cells in the pancreas, without interfering with their proliferation and expansion in the draining pancreatic lymph nodes. Pancreata from NOD-gld/+ mice contained B cells that expressed CD5 and produced IL-10, which was critical for maintenance of the disease resistance because its neutralization with an IL-10 receptor-blocking monoclonal antibody allowed accumulation of CD4 T cells in the pancreas and led to insulitis development. The results provide novel insights into the pathogenesis of T1D that could have important therapeutic implications.

SUBMITTER: Xiao Z

PROVIDER: S-EPMC3157218 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Inhibition of Fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development.

Xiao Zuoxiang Z Mohamood Abdiaziz S AS Uddin Sophia S Gutfreund Rachel R Nakata Chiaki C Marshall Andrew A Kimura Hiroaki H Caturegli Patrizio P Womer Karl L KL Huang Yanfei Y Jie Chunfa C Chakravarti Shukti S Schneck Jonathan P JP Yagita Hideo H Hamad Abdel Rahim A AR

The American journal of pathology 20110615 2

Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of pancreatic insulin-producing β cells by autoreactive T cells early in life. Despite daily insulin injections, patients typically develop cardiovascular and other complications; and intensive efforts are being directed toward identifying therapeutic targets to prevent the disease without directly impinging on the host defense. Fas ligand (FasL) is one potential target. Fas-FasL interactions primarily regulate T-c ...[more]

PMID: 21718680

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Project description:Background:A link between selenium deficiency and inflammatory skin diseases have been noted by many, but this link is still not well understood. We have previously studied the efficacy of ceramide analogs, based on the fire ant venom Solenopsin A, against our psoriasis animal model. Treatment of animals with solenopsin analogs resulted in significantly improved skin as well as in a coordinate downregulation of selenoproteins, namely Glutathione Peroxidase 4 (GPX4). We thus hypothesize that ferroptosis may be a physiologic process that may protect the skin from both inflammatory and neoplastic processes.Methods:We analyze and compare gene expression profiles in the GEO database from clinical skin samples taken from healthy patients and psoriasis patients (both involved and noninvolved skin lesions). We validated the gene expression results against a second, independent, cohort from the GEO database.Results:Significant reduction in gene expression of GPX4, elevated expression of Nrf2 downstream targets, and expression profiles mirroring erastin-inhibition of Cystine/Glutamate Antiporter-System XC activity in psoriatic skin lesions, compared to both noninvolved skin and healthy patient samples, suggest an innately inducible mechanism of ferroptosis.Conclusions:We present data that may indicate selenoproteins, particularly GPX4, in resolving inflammation and skin cancer, including the novel hypothesis that the human organism may downregulate GPX4 and reactive oxygen (REDOX) regulating proteins in the skin as a way of resolving psoriasis and nonmelanoma skin cancer through increased reactive oxygen species. Further studies are needed to investigate ferroptosis as a possible physiologic mechanism for eliminating inflammatory and malignant tissues.General significance:This study provides a fresh framework for understanding the seemingly contradictory effects of selenium supplementation. In addition, it offers a novel explanation of how physiologic upregulation of ferroptosis and downregulation of selenoprotein synthesis may mediate resolution of inflammation and carcinogenesis. This is of therapeutic significance.

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Inhibition of Fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development.

Publications

Inhibition of Fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development.

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