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Kidney Int. 2017 May;91(5):1146-1158. doi: 10.1016/j.kint.2016.10.037. Epub 2017 Jan 19.

Glomerular common gamma chain confers B- and T-cell-independent protection against glomerulonephritis.

Author information

1
Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France; Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
2
Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France; Plateforme d'imagerie et de cytométrie de l'hôpital Tenon, Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France.
3
Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France.
4
Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
5
Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
6
Inserm, UMR 1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
7
Inserm U1020, Université Paris Descartes, Paris, France.
8
Weill Cornell Medicine, The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, New York, New York, USA.
9
Unité Immunité Innée, Institut Pasteur, Inserm U1223, Paris, France.
10
Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France; Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France; Weill Cornell Medicine, The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, New York, New York, USA. Electronic address: laurent.mesnard@aphp.fr.

Abstract

Crescentic glomerulonephritis is a life-threatening renal disease that has been extensively studied by the experimental anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN) model. Although T cells have a significant role in this model, athymic/nude mice and rats still develop severe renal disease. Here we further explored the contribution of intrinsic renal cells in the development of T-cell-independent GN lesions. Anti-GBM-GN was induced in three strains of immune-deficient mice (Rag2-/-, Rag2-/-Il2rg-/-, and Rag2-/-Il2rb-/-) that are devoid of either T/B cells or T/B/NK cells. The Rag2-/-Il2rg-/- or Rag2-/-Il2rb-/- mice harbor an additional deletion of either the common gamma chain (γC) or the interleukin-2 receptor β subunit (IL-2Rβ), respectively, impairing IL-15 signaling in particular. As expected, all these strains developed severe anti-GBM-GN. Additionally, bone marrow replenishment experiments allowed us to deduce a protective role for the glomerular-expressed γC during anti-GBM-GN. Given that IL-15 has been found highly expressed in nephritic kidneys despite the absence of lymphocytes, we then studied this cytokine in vitro on primary cultured podocytes from immune-deficient mice (Rag2-/-Il2rg-/- and Rag2-/-Il2rb-/-) compared to controls. IL-15 induced downstream activation of JAK1/3 and SYK in primary cultured podocytes. IL-15-dependent JAK/SYK induction was impaired in the absence of γC or IL-2Rβ. We found γC largely induced on podocytes during human glomerulonephritis. Thus, renal lesions are indeed modulated by intrinsic glomerular cells through the γC/IL-2Rβ receptor response, to date classically described only in immune cells.

KEYWORDS:

IL-15; IL-2Rβ; glomerulonephritis; lymphocyte; podocyte; γC chain

PMID:
28111009
DOI:
10.1016/j.kint.2016.10.037
[Indexed for MEDLINE]

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