Mutation in the rat interleukin 34 gene impacts macrophage development, homeostasis and inflammation
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ABSTRACT:
PROVIDER: PRJEB90514 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR15168733_1.fastq.gz | Fastqsanger.gz | |||
| ERR15168733_2.fastq.gz | Fastqsanger.gz | |||
| ERR15168734_1.fastq.gz | Fastqsanger.gz | |||
| ERR15168734_2.fastq.gz | Fastqsanger.gz | |||
| ERR15168735_1.fastq.gz | Fastqsanger.gz |
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Project description:The development of most macrophages depends on the colony-stimulating factor 1 (CSF-1) receptor, which has two ligands: CSF-1 and interleukin-34 (IL-34). While IL-34 is required for the homeostasis of microglia, the parenchymal macrophages in the central nervous system (CNS), it is unclear whether brain border-associated macrophages (BAMs) also depend on this cytokine. Here, we demonstrated that the embryonic development of murine BAMs in the choroid plexus, leptomeninges, and perivascular spaces required CSF-1, while IL-34 was critical for their maintenance in adulthood. In the brain, Il34 was expressed by mural cells and perivascular fibroblasts, and its transgenic deletion in these cells interrupted BAM maintenance. Il34-deficiency coincided with transcriptional changes in vascular cells, leading to increased flow velocity and vasomotion in pial and penetrating arterioles. Similarly, Mrc1CreCsf1rfl/fl mice lacking CD206+ perivascular BAMs exhibited increased hemodynamics in arterial networks. These findings reveal a crosstalk between vascular cells and CNS macrophages regulating cerebrovascular function.
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Project description:Gastrointestinal (GI) tract graft versus host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remains a major goal in this disease. Herein, we have identified interleukin 34 (IL-34) as a tissue-intrinsic regulatory cytokine that is able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages towards a proinflammatory phenotype and augmented the accumulation of pathogenic CD4+ GM-CSF+ T cells within the colon. Conversely, the administration of recombinant IL-34 significantly reduced GVHD mortality and inflammation in the GI tract which was dependent upon the expression of apolipoprotein E (ApoE) in donor macrophages. Complementary genetic and imaging approaches demonstrated that intestinal epithelial cells were the biologically relevant source of IL-34. Colonic biopsies from patients with GVHD also revealed expression of IL-34 in intestinal epithelial cells, as well as ApoE in lamina propria macrophages, validating similar cellular localization in humans. Thus, these studies define IL-34 as an intestinal epithelial-derived cytokine that regulates macrophage polarization in an ApoE-dependent manner, positioning this cytokine as a key regulator of GVHD in the GI tract and a potential therapeutic target for amelioration of this disease.
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Project description:This SuperSeries is composed of the following subset Series: GSE24992: Drosophila brain microRNA expression with age: miRNA profiling GSE25007: Drosophila brain gene expression with age: mRNA profiling GSE25008: Drosophila brain gene expression between wildtype and miR-34 null flies Refer to individual Series. Aging is the most prominent risk factor for human neurodegenerative disease, but underlying mechanisms that connect two processes are less well characterized. With age, the brain undergoes functional decline and perhaps degeneration. Such decline may not just contribute to normal aging, but also enhance susceptibility to and progression of age-related neurodegenerative diseases. Therefore, defining intrinsic factors and pathways that underline the normal integrity of the adult nervous system may lead to insights that potentially link aging and neurodegeneration. Here, we report a highly conserved microRNA (miRNA), miR-34, as a modulator of aging and neurodegeneration. Using Drosophila, we show that fly miR-34 expression is brain-enriched and strikingly upregulated with age. Functional studies reveal that, whereas animals without miR-34 are normal as young adults, upon aging, they gradually show late-onset deficits characteristic of accelerated brain aging; these include a transcriptional signature of aged animals, coupled with rapid functional decline, loss of brain integrity, followed by a catastrophic decline in adult viability. Moreover, upregulation of miR-34 protects against neurodegeneration induced by pathogenic human polyglutamine (polyQ) disease protein. We next reveal a dramatic effect of miR-34 to silence the Eip74EF gene of steroid hormone pathways in the adult, which is crucial to maintain the normal aging. Collectively, these data define a miR-34-mediated mechanism that specifically affects long-term integrity of the adult nervous system. miR-34 function in Drosophila may thus present a link that functionally connects aging and neurodegeneration. Our studies implicate essential roles of miRNA- dependent pathways in maintenance of the adult brain, disease pathogenesis and healthy aging.
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