RESUMO
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
Assuntos
Envelhecimento , Interleucina-11 , Longevidade , Transdução de Sinais , Animais , Feminino , Masculino , Camundongos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Fragilidade/genética , Fragilidade/metabolismo , Fragilidade/prevenção & controle , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Interleucina-11/antagonistas & inibidores , Interleucina-11/deficiência , Interleucina-11/genética , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Longevidade/efeitos dos fármacos , Longevidade/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Humanos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologiaRESUMO
Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor ß1 (TGFß1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFß1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFß1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
Assuntos
Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , Fibrose/metabolismo , Fibrose/patologia , Interleucina-11/metabolismo , Animais , Comunicação Autócrina , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/induzido quimicamente , Coração , Humanos , Interleucina-11/antagonistas & inibidores , Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Rim/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Escores de Disfunção Orgânica , Biossíntese de Proteínas , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Transgenes/genéticaRESUMO
BACKGROUND & AIMS: We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH. METHODS: We stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1-/-) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays. RESULTS: HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1-/- mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/- mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1. CONCLUSIONS: Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.
Assuntos
Anticorpos Neutralizantes/farmacologia , Hepatite/prevenção & controle , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/antagonistas & inibidores , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Morte Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos , Células THP-1RESUMO
Current therapies for the autoimmune demyelinating disease multiple sclerosis (MS) target inflammation, but do not directly address neuroprotection or lesion repair. Cytokines of the gp130 family regulate survival and differentiation of both neural and immune cells, and we recently identified expression of the family member IL-11 in active MS plaques. In this study, we show that IL-11 regulates the clinical course and neuropathology of experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of MS. Importantly, the effects of IL-11 are achieved via a combination of immunoregulation and direct neuroprotection. IL-11R-alpha-null (IL-11Ralpha(-/-)) mice displayed a significant increase in clinical severity and neuropathology of experimental autoimmune encephalomyelitis compared with wild-type littermates. Inflammation, demyelination, and oligodendrocyte and neuronal loss were all exacerbated in IL-11Ra(-/-) animals. Conversely, wild-type mice treated with IL-11 displayed milder clinical signs and neuropathology than vehicle-treated controls. In cocultures of murine myelin oligodendrocyte glycoprotein(35-55)-specific CD4+ T lymphocytes and CD11c+ APCs, IL-11 treatment resulted in a significant decrease in T cell-derived effector cytokine production. This effect was generated via modulation of CD11c+ APC-mediated lymphocyte activation, and was associated with a decrease in the size of the CD11c+ cell population. Conversely, IL-11 strongly reduced apoptosis and potentiated mitosis in primary cultures of mouse oligodendrocyte progenitors. Collectively, these data reveal that IL-11 regulates inflammatory demyelination via a unique combination of immunoregulation and neuroprotection. IL-11 signaling may represent a therapeutic avenue to restrict CNS inflammation and potentiate oligodendrocyte survival in autoimmune demyelinating disease.
Assuntos
Autoanticorpos/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Mediadores da Inflamação/fisiologia , Interleucina-11/fisiologia , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Autoanticorpos/fisiologia , Antígeno CD11c/biossíntese , Técnicas de Cocultura , Encefalomielite Autoimune Experimental/patologia , Humanos , Subunidade alfa de Receptor de Interleucina-11/biossíntese , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Fármacos Neuroprotetores/metabolismo , Oligodendroglia/imunologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Índice de Gravidade de Doença , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Células-Tronco/patologia , Técnicas de Cultura de TecidosRESUMO
Hormonal contraceptives are unsuitable for many women; thus, the development of new, nonhormonal contraceptives is of great interest. In women, uterine epithelial expression of interleukin 11 (IL11) and its receptor (IL11RA) suggests IL11 is critical for blastocyst attachment during implantation. Il11ra-deficient mice are infertile due to a defective decidualization response to the blastocyst, leading to total pregnancy loss. We examined the effect of administering a PEGylated IL11 antagonist, PEGIL11A (where PEG is polyethylene glycol), on pregnancy outcomes in mice and IL11 signaling in human endometrial epithelial cells (HES). PEGIL11A was detected in sera up to 72 h after intraperitoneal (IP) injection versus up to 2 h for the non-PEGylated antagonist. Following IP injection, PEGIL11A localized to uterine decidual cells and reduced immunoreactive cyclin D3 (IL11 decidual target). To inhibit IL11 action during early decidualization, PEGIL11A or control were administered IP on Days 3-6 (beginning just prior to maximal decidual Il11 expression). On Day 6, mesometrial decidualization was disturbed in PEGIL11A-treated animals with regions of hemorrhage visible in the mesometrial decidua. On Day 10, severe decidual destruction was visible: implantation sites contained significant hemorrhage, and the uterine luminal epithelium had reformed, suggesting a return to estrous cycling. These results demonstrate that PEGIL11A blocked IL11 action in the decidua during early decidualization, which totally abolished pregnancy and which is equivalent to the Il11ra(-/-) mouse. PEGIL11A significantly diminished STAT3 phosphorylation in HES cells in vitro (P < or = 0.05). This study provides valuable information for PEGIL11A that could lead to the development of this protein as a nonhormonal contraceptive.
Assuntos
Interleucina-11/antagonistas & inibidores , Útero/imunologia , Útero/patologia , Animais , Linhagem Celular , Anticoncepção Imunológica/métodos , Ciclina D3 , Ciclinas/metabolismo , Decídua/efeitos dos fármacos , Decídua/imunologia , Decídua/patologia , Implantação do Embrião/imunologia , Endométrio/efeitos dos fármacos , Endométrio/imunologia , Endométrio/metabolismo , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Gravidez , Resultado da Gravidez , Fator de Transcrição STAT3/metabolismo , Células Estromais/imunologia , Células Estromais/patologia , Útero/efeitos dos fármacos , Útero/metabolismoRESUMO
Interleukin 11 receptor alpha (Il11ra) null mice are infertile due to defective decidualization and abnormal trophoblast invasion. We have previously shown in these mice that downregulation of decidual proteinase inhibitors plays a role in uncontrolled trophoblast invasion. However, the decidua is abnormally smaller in pseudopregnant Il11ra null mice, where trophoblast invasion is not a factor. Here, we examined whether defective decidualization is due to dysregulation of key molecules involved in decidual cell growth and differentiation. We found a dramatic downregulation of cyclin D3 in Il11ra null mice. We also found that IL11 robustly stimulates the expression of cyclin D3 in cell culture. CDK4 and CDK6, known partners of cyclin D3, are not affected. Immunolocalization studies show absence of cyclin D3 in the mesometrial site and absence of differentiated polyploid cells in the antimesometrial site of Il11ra null mice. We also examined the expression of cell differentiation factors CDKN1A (p21) and CDKN1B (p27), and found that in both in vivo and cell culture the expression of CDKN1A (p21) but not CDKN1B (p27) is under the control of IL11. Another clear target of IL11 in the decidua is BIRC5 (Survivin), whose expression is repressed in the decidua of Il11ra null mice and stimulated by IL11 in cell culture. Taken together, these results provide, at least in part, an explanation for the defective small decidua of mice lacking the Il11ra gene, and reveal for the first time that cyclin D3, CDKN1A (p21), and BIRC5 (Survivin) are targets of IL11 in the decidua.