Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice

Sambit Kumar Nanda, Tsvetana Petrova, Francesco Marchesi, Marek Gierlinski, Momchil Razsolkov, Katherine L. Lee, Stephen W. Wright, Vikram R. Rao, Philip Cohen (Lead / Corresponding author), J. Simon C. Arthur (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

We report that TLR7, IL-6, and the adaptive immune system are essential for autoimmunity and glomerulonephritis but not for liver pathology in mice expressing the ubiquitin-binding-defective ABIN1[D485N] mutant. The blood and organs of ABIN1[D485N] mice have exceptionally high numbers of patrolling monocytes (pMo), which develop independently of IL-6 and the adaptive immune system. They are detectable in the blood months before autoimmunity and organ pathology are seen and may have diagnostic potential. The splenic pMo, inflammatory monocytes (iMo), and neutrophils of ABIN1[D485N] mice expressed high levels of mRNAs encoding proteins released during NETosis, which together with the high numbers of monocyte-derived dendritic cells (MoDCs) may drive the liver pathology in ABIN1[D485N] mice, and contribute to the pathology of other organs. The splenic iMo of ABIN1[D485N] mice displayed high expression of mRNAs encoding proteins controlling cell division and were actively dividing; this may underlie the increased pMo and MoDC numbers, which are derived from iMo. An orally active IRAK4 inhibitor suppressed all facets of the disease phenotype and prevented the increase in pMo numbers.

Original languageEnglish
Article numbere201900533
Pages (from-to)1-19
Number of pages19
JournalLife Science Alliance
Volume2
Issue number6
Early online date6 Nov 2019
DOIs
Publication statusPublished - 1 Dec 2019

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glomerulonephritis
Pathology
pathology
Glomerulonephritis
Liver
monocytes
Monocytes
liver
Immune system
mice
immune system
Interleukin-6
Blood
blood
cells
Messenger RNA
protein
autoimmunity
Ubiquitin
dendritic cells

Cite this

@article{71293ba509cf44889bff6a53af3a06e1,
title = "Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice",
abstract = "We report that TLR7, IL-6, and the adaptive immune system are essential for autoimmunity and glomerulonephritis but not for liver pathology in mice expressing the ubiquitin-binding-defective ABIN1[D485N] mutant. The blood and organs of ABIN1[D485N] mice have exceptionally high numbers of patrolling monocytes (pMo), which develop independently of IL-6 and the adaptive immune system. They are detectable in the blood months before autoimmunity and organ pathology are seen and may have diagnostic potential. The splenic pMo, inflammatory monocytes (iMo), and neutrophils of ABIN1[D485N] mice expressed high levels of mRNAs encoding proteins released during NETosis, which together with the high numbers of monocyte-derived dendritic cells (MoDCs) may drive the liver pathology in ABIN1[D485N] mice, and contribute to the pathology of other organs. The splenic iMo of ABIN1[D485N] mice displayed high expression of mRNAs encoding proteins controlling cell division and were actively dividing; this may underlie the increased pMo and MoDC numbers, which are derived from iMo. An orally active IRAK4 inhibitor suppressed all facets of the disease phenotype and prevented the increase in pMo numbers.",
author = "Nanda, {Sambit Kumar} and Tsvetana Petrova and Francesco Marchesi and Marek Gierlinski and Momchil Razsolkov and Lee, {Katherine L.} and Wright, {Stephen W.} and Rao, {Vikram R.} and Philip Cohen and Arthur, {J. Simon C.}",
note = "The research conducted by SK Nanda, T Petrova, F Marchesi, and M Gierlinski was funded by grants from the UK Medical Research Council (MR/R021406/1) (to P Cohen and JSC Arthur) and the Wellcome Trust (209380/Z/17/Z) (to P Cohen). Some of the studies were carried out while T Petrova was the recipient of a Wellcome Trust Prize Studentship (105309/Z/14/Z). M Razsolkov holds a UK Medical Research Council studentship (MR/N013735/1). The work performed by VR Rao, K Lee, and SW Wright was funded by the Research & Development budget of Pfizer Inc. {\circledC} 2019 Nanda et al.",
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TY - JOUR

T1 - Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice

AU - Nanda, Sambit Kumar

AU - Petrova, Tsvetana

AU - Marchesi, Francesco

AU - Gierlinski, Marek

AU - Razsolkov, Momchil

AU - Lee, Katherine L.

AU - Wright, Stephen W.

AU - Rao, Vikram R.

AU - Cohen, Philip

AU - Arthur, J. Simon C.

N1 - The research conducted by SK Nanda, T Petrova, F Marchesi, and M Gierlinski was funded by grants from the UK Medical Research Council (MR/R021406/1) (to P Cohen and JSC Arthur) and the Wellcome Trust (209380/Z/17/Z) (to P Cohen). Some of the studies were carried out while T Petrova was the recipient of a Wellcome Trust Prize Studentship (105309/Z/14/Z). M Razsolkov holds a UK Medical Research Council studentship (MR/N013735/1). The work performed by VR Rao, K Lee, and SW Wright was funded by the Research & Development budget of Pfizer Inc. © 2019 Nanda et al.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - We report that TLR7, IL-6, and the adaptive immune system are essential for autoimmunity and glomerulonephritis but not for liver pathology in mice expressing the ubiquitin-binding-defective ABIN1[D485N] mutant. The blood and organs of ABIN1[D485N] mice have exceptionally high numbers of patrolling monocytes (pMo), which develop independently of IL-6 and the adaptive immune system. They are detectable in the blood months before autoimmunity and organ pathology are seen and may have diagnostic potential. The splenic pMo, inflammatory monocytes (iMo), and neutrophils of ABIN1[D485N] mice expressed high levels of mRNAs encoding proteins released during NETosis, which together with the high numbers of monocyte-derived dendritic cells (MoDCs) may drive the liver pathology in ABIN1[D485N] mice, and contribute to the pathology of other organs. The splenic iMo of ABIN1[D485N] mice displayed high expression of mRNAs encoding proteins controlling cell division and were actively dividing; this may underlie the increased pMo and MoDC numbers, which are derived from iMo. An orally active IRAK4 inhibitor suppressed all facets of the disease phenotype and prevented the increase in pMo numbers.

AB - We report that TLR7, IL-6, and the adaptive immune system are essential for autoimmunity and glomerulonephritis but not for liver pathology in mice expressing the ubiquitin-binding-defective ABIN1[D485N] mutant. The blood and organs of ABIN1[D485N] mice have exceptionally high numbers of patrolling monocytes (pMo), which develop independently of IL-6 and the adaptive immune system. They are detectable in the blood months before autoimmunity and organ pathology are seen and may have diagnostic potential. The splenic pMo, inflammatory monocytes (iMo), and neutrophils of ABIN1[D485N] mice expressed high levels of mRNAs encoding proteins released during NETosis, which together with the high numbers of monocyte-derived dendritic cells (MoDCs) may drive the liver pathology in ABIN1[D485N] mice, and contribute to the pathology of other organs. The splenic iMo of ABIN1[D485N] mice displayed high expression of mRNAs encoding proteins controlling cell division and were actively dividing; this may underlie the increased pMo and MoDC numbers, which are derived from iMo. An orally active IRAK4 inhibitor suppressed all facets of the disease phenotype and prevented the increase in pMo numbers.

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U2 - 10.26508/lsa.201900533

DO - 10.26508/lsa.201900533

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VL - 2

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JF - Life Science Alliance

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