RNA-seq of inflammatory monocytes, patrolling monocytes and neutrophils in wild type and ABIN1[D485N] mice
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PROVIDER: PRJEB33670 | ENA |
REPOSITORIES: ENA
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Project description:We have previously generated ABIN1[D485N] knock-in mice that appear relatively normal for 2 months after birth, but develop large spleen at 3 months, which is followed by the appearance of high levels of antibodies against self DNA and self-nuclear antigens and severe inflammation of the kidney and other tissues after 4-5 months, hall marks of lupus like autoimmunity. Autoimmunity in ABIN1[D485N] mice appears to be caused by hyper activation of pathogen sensing Toll-like Receptor (TLR) pathway, because the phenotype of the ABIN1[D485N] mice is completely suppressed by crossing them to mice that are either lacking or expressing functionally defective proteins, which play key role in TLR signalling. MyD88 KO, IRAK4 or IRAK1 kinase-inactive knock-in mice. However, cell type(s) required to drive lupus, and how this contributes to the development of the pathology, is unknown. Recently, we have identified atypical myeloid (CD11b+ve) populations in the blood, lungs liver, kidney and spleen of ABIN1[D485N] mice. Importantly, these cells are detectable at four weeks, at least two months before auto-antibodies are detected in the serum. More detailed flow cytometry analysis of these cells revealed that, in the blood, the majority were CD115+ve and these cells could be further subdivided into Ly6C+ve and Ly6C-ve, which are characteristics of the inflammatory and patrolling monocytes, respectively. While in the lungs and spleen of WT mice the Ly6C-ve CD115+ve (patrolling monocytes) are almost absent, in the ABIN1[D485N] mice this population is more than 20-fold increased. There is also increase in the number of neutrophil population (CD11b+ GR-1hi) in the spleen of the ABIN1[D485N] mice. Although we have shown that the formation of these atypical myeloid cells proceeds the development of auto-antibodies and organ inflammation in the ABIN1[D485] mice, the signalling pathway leading to formation of these cells and their role in autoimmunity is unknown. We therefore undertook RNAseq analysis to characterise these cells in more detail. The atypical CD11b+ve cells present in spleen of ABIN1[D485N] mice are heterogeneous with three major populations, neutrophils (CD11b+ GR-1hi), Ly6C+veCD115+ve cells and Ly6C-veCD115+ve. How these cell populations in ABIN1[D485N] mice relate to one another, and whether they share a common precursor is unknown. In order to profile the cells, the neutrophils, Ly6C+veCD115+ve cells and Ly6C-veCD115+ve populations were purified by cell sorting and RNAseq analysis carried out. The RNA seq analysis was carried out with at least four replicate samples from each cell populations from ABIN1[D485N] and WT controls.
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