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1.
Eur J Immunol ; 48(8): 1364-1375, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29671873

RESUMO

Innate lymphoid cells (ILCs) are important regulators of the immune response and play a crucial role in the restoration of tissue homeostasis after injury. GATA-3+ IL-13- and IL-5-producing group 2 innate lymphoid cells (ILC2s) have been shown to promote tissue repair in barrier organs, but despite extensive research on ILCs in the recent years, their potential role in autoimmune diseases is still incompletely understood. In the present study, we investigate the role of ILC2s in the MRL/MpJ-Faslpr (MRL-lpr) mouse model for severe organ manifestation of systemic lupus erythematosus (SLE). We show that in these MRL-lpr mice, progression of lupus nephritis is accompanied with a reduction of ILC2 abundance in the inflamed renal tissue. Proliferation/survival and cytokine production of kidney-residing ILC2s was suppressed by IFN-γ and, to a lesser extent, by IL-27 which were produced by activated T cells and myeloid cells in the nephritic kidney, respectively. Most importantly, restoration of ILC2 numbers by IL-33-mediated expansion ameliorated lupus nephritis and prevented mortality in MRL-lpr mice. In summary, we show here that development of SLE-like kidney inflammation leads to a downregulation of the renal ILC2 response and identify an ILC2-expanding therapy as a promising treatment approach for autoimmune diseases.


Assuntos
Interferon gama/metabolismo , Interleucina-33/metabolismo , Interleucinas/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Linfócitos T/imunologia , Animais , Células Cultivadas , Regulação para Baixo , Fator de Transcrição GATA3/metabolismo , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Rim/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr
2.
J Am Soc Nephrol ; 28(7): 2068-2080, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28154198

RESUMO

Innate lymphoid cells (ILCs) have an important role in the immune system's response to different forms of infectious and noninfectious pathologies. In particular, IL-5- and IL-13-producing type 2 ILCs (ILC2s) have been implicated in repair mechanisms that restore tissue integrity after injury. However, the presence of renal ILCs in humans has not been reported. In this study, we show that ILC populations are present in the healthy human kidney. A detailed characterization of kidney-residing ILC populations revealed that IL-33 receptor-positive ILC2s are a major ILC subtype in the kidney of humans and mice. Short-term IL-33 treatment in mice led to sustained expansion of IL-33 receptor-positive kidney ILC2s and ameliorated adriamycin-induced glomerulosclerosis. Furthermore, the expansion of ILC2s modulated the inflammatory response in the diseased kidney in favor of an anti-inflammatory milieu with a reduction of pathogenic myeloid cell infiltration and a marked accumulation of eosinophils that was required for tissue protection. In summary, kidney-residing ILC2s can be effectively expanded in the mouse kidney by IL-33 treatment and are central regulators of renal repair mechanisms. The presence of ILC2s in the human kidney tissue identifies these cells as attractive therapeutic targets for CKD in humans.


Assuntos
Interleucina-33/fisiologia , Nefropatias/imunologia , Glomérulos Renais/patologia , Linfócitos/imunologia , Animais , Proliferação de Células , Células Cultivadas , Progressão da Doença , Feminino , Humanos , Imunidade Inata , Interleucina-33/uso terapêutico , Nefropatias/prevenção & controle , Linfócitos/classificação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Esclerose/imunologia , Esclerose/prevenção & controle
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