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1.
J Exp Med ; 217(10)2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32716519

RESUMO

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXRαß-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαß's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαß for cholesterol efflux, thymic epithelial cells (TECs) use LXRαß for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαß protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαß limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαß governs T lymphocyte education and illuminate LXRαß's indispensable roles in adaptive immunity.


Assuntos
Receptores X do Fígado/fisiologia , Fígado/metabolismo , Linfócitos T/fisiologia , Timo/fisiologia , Imunidade Adaptativa , Animais , Apoptose , Feminino , Citometria de Fluxo , Homeostase , Humanos , Metabolismo dos Lipídeos , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T/metabolismo , Timo/metabolismo
2.
Nat Med ; 22(8): 945-51, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27428900

RESUMO

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threatens the organism with anemia and iron toxicity. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 (LY6C1, also known as Ly-6C) ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1 (FPN1, encoded by SLC40A1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1(+)Tim-4(neg) macrophages are transient, reside alongside embryonically derived T cell immunoglobulin and mucin domain containing 4 (Timd4, also known as Tim-4)(high) Kupffer cells (KCs), and depend on the growth factor Csf1 and the transcription factor Nrf2 (encoded by Nfe2l2). The spleen, likewise, recruits iron-loaded Ly-6C(high) monocytes, but these do not differentiate into iron-recycling macrophages, owing to the suppressive action of Csf2. The accumulation of a transient macrophage population in the liver also occurs in mouse models of hemolytic anemia, anemia of inflammation, and sickle cell disease. Inhibition of monocyte recruitment to the liver during stressed erythrocyte delivery leads to kidney and liver damage. These observations identify the liver as the primary organ that supports rapid erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.


Assuntos
Eritrócitos/metabolismo , Hepatócitos/metabolismo , Ferro/metabolismo , Células de Kupffer/metabolismo , Fígado/metabolismo , Anemia , Anemia Hemolítica , Anemia Falciforme , Animais , Antígenos Ly/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Eritrócitos/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Inflamação , Células de Kupffer/citologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Monócitos/citologia , Monócitos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Baço
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