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12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice.

ABSTRACT: 12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice.

PROVIDER: PRJNA1137967 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29896700_1.fastq.gz	Fastqsanger.gz
	SRR29896700_2.fastq.gz	Fastqsanger.gz
	SRR29896701_1.fastq.gz	Fastqsanger.gz
	SRR29896701_2.fastq.gz	Fastqsanger.gz
	SRR29896702_1.fastq.gz	Fastqsanger.gz

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12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice

Project description:12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice

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12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice.

Project description:Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12gene. Our findings demonstrate that VLX-1005, a potent 12-LOX inhibitor, effectively delays the onset of autoimmune diabetes in human gene replacement non-obese diabetic (NOD) mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecules PD-L1 and PD-1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets from inhibitor-treated mice revealed significant alteration of cytokine-responsive pathways. RNA sequencing of polarized proinflammatory macrophages showed that VLX-1005 significantly reduced the interferon response. This study highlights a functional equivalence of human ALOX12 and mouse Alox15 in T1D pathogenesis. Our studies provide a platform for the preclinical evaluation of LOX inhibitors and supports the development of 12-LOX inhibitors as a therapeutic strategy for T1D and other inflammatory diseases.

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12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice.

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