RESUMO
Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγΔKRKR) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγΔKRKR in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγΔKRKR mice lacking the EBD by using CRISPR-Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation.
Assuntos
Citocinas , Neoplasias , Camundongos , Animais , Citocinas/metabolismo , Interferon gama/metabolismo , Transdução de Sinais , Matriz Extracelular/metabolismoRESUMO
The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ-GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.
Assuntos
Vasos Sanguíneos/crescimento & desenvolvimento , Hipóxia Celular/imunologia , Interferon gama/imunologia , Isquemia/imunologia , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Remodelação Vascular , Animais , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/metabolismo , Linhagem Celular Tumoral , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Feminino , Interferon gama/biossíntese , Microscopia Intravital , Isquemia/metabolismo , Isquemia/patologia , Masculino , Camundongos , Necrose , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Interferon/metabolismo , Células Estromais/imunologia , Células Estromais/metabolismo , Especificidade por Substrato , Cicatrização , Receptor de Interferon gamaRESUMO
The contribution of molecules such as perforin, IFN-γ (IFNγ), and particularly Fas ligand (FasL) by transferred CD8(+) effector T (T(E)) cells to rejection of large, established tumors is incompletely understood. Efficient attack against large tumors carrying a surrogate tumor antigen (mimicking a "passenger" mutation) by T(E) cells requires action of IFNγ on tumor stroma cells to avoid selection of antigen-loss variants. Because "cancer-driving" antigens (CDAs) are rarely counterselected, IFNγ may be expected to be dispensable in elimination of cancers by targeting a CDA. Here, initial regression of large, established tumors required neither IFNγ, FasL, nor perforin by transferred CD8(+) T(E) cells targeting Simian Virus (SV) 40 large T as CDA. However, cytotoxic T(E) cells lacking IFNγ or FasL could not prevent relapse despite retention of the rejection antigen by the cancer cells. Complete tumor rejection required IFNγ-regulated Fas by the tumor stroma. Therefore, T(E) cells lacking IFNγ or FasL cannot prevent progression of antigenic cancer because the tumor stroma escapes destruction if its Fas expression is down-regulated.
Assuntos
Neoplasias/imunologia , Neoplasias/patologia , Receptor fas/metabolismo , Animais , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunoterapia Adotiva , Interferon gama/deficiência , Interferon gama/genética , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Neoplasias/metabolismo , Neoplasias/terapia , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T Citotóxicos/imunologia , Receptor de Interferon gamaRESUMO
Mice deficient either in subtypes of immune cells, cytokines or lytic pathways have been subjected to chemical carcinogenesis by methylcholanthrene to evaluate whether these components of the immune system affect tumor development. Inbred mice of the same genotype but from different sources differed in tumor development in magnitude comparable to that previously attributed to differences in immunocompetence. This suggested that genetic drift between separate inbred colonies of mice and/or environmental factors (e.g., transport of the animals) influenced carcinogenesis. Therefore, littermates were used as control in subsequent experiments. Although deficiency of T-cells, NKT-cells, perforin, Fas-ligand, TNF-α-receptor failed to reveal significant differences in tumor development, the presence of B-cells and IL-4 enhanced tumor development under similar experimental conditions.
Assuntos
Linfócitos B/metabolismo , Transformação Celular Neoplásica/genética , Proteína Ligante Fas/genética , Interleucina-4/genética , Perforina/genética , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/genética , Animais , Linfócitos B/imunologia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/imunologia , Meio Ambiente , Proteína Ligante Fas/metabolismo , Feminino , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-4/metabolismo , Masculino , Metilcolantreno , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Perforina/metabolismo , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
To enhance protection from pathogens, housing conditions have been improved constantly. We wanted to test whether various environmental conditions and caging systems affect serum cytokine levels of immunodeficient mice differently than they affect immunocompetent control animals. We compared serum cytokine levels of immunodeficient and immunocompetent mice kept in three different environments: a specific pathogen free (SPF) breeding barrier with open cages. An SPF experimental unit with individually ventilated cages. An experimental semi-barrier with open cages. Serum from Rag1(-/-), µMT(-/-), IFN-γR(-/-), IFN-γ(-/-), IL-4(-/-), the heterozygous controls and wild type C57BL/6 or BALB/c mice was analyzed for the presence of 10 cytokines (IL-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IFN-γ, TNF-α and GM-CSF). No major changes in cytokine levels were detected in mice exposed to different housing conditions. However, irrespective of immunodeficiency at 4 weeks of age a number of mice from the breeding colonies with a targeted mutation (TM), both -/- and +/- mice, showed a statistically significant elevation of some cytokines (primarily IL-1α, IL-5) when compared to wild type BALB/c and C57BL/6 mice. We conclude that under SPF conditions, immunodeficient mice can be kept either in open caging or IVC systems without affecting serum cytokine levels. The more important conclusion, however, stems from the observation that there is a significant difference in serum cytokine levels between wild type and mice carrying either one or two alleles of a targeted mutation (either -/- and +/- mice). This suggests an altered base-line inflammatory responsiveness in the TM-breeding colonies.
Assuntos
Cruzamento/métodos , Citocinas/sangue , Abrigo para Animais , Imunocompetência , Organismos Livres de Patógenos Específicos/imunologia , Animais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , MutaçãoRESUMO
Tumor-associated lymphatic vessels promote metastasis and regulate antitumor immune responses. Here, we assessed the impact of cytotoxic T cells on the local lymphatic vasculature and concomitant tumor dissemination during an antitumor response. Interferon-γ (IFN-γ) released by effector T cells enhanced the expression of immunosuppressive markers by tumor-associated lymphatic endothelial cells (LECs). However, at higher effector T cell densities within the tumor, T cell-based immunotherapies induced LEC apoptosis and decreased tumor lymphatic vessel density. As a consequence, lymphatic flow was impaired, and lymph node metastasis was reduced. Mechanistically, T cell-mediated tumor cell death induced the release of tumor antigens and cross-presentation by tumor LECs, resulting in antigen-specific LEC killing by T cells. When LECs lacked the IFN-γ receptor expression, LEC killing was abrogated, indicating that IFN-γ is indispensable for reducing tumor-associated lymphatic vessel density and drainage. This study provides insight into how cytotoxic T cells modulate tumor lymphatic vessels and may help to improve immunotherapeutic protocols.
Assuntos
Células Endoteliais , Interferon gama , Antígenos de Neoplasias , Apresentação Cruzada , Células Endoteliais/metabolismo , Humanos , Interferon gama/metabolismo , Metástase LinfáticaRESUMO
It has been shown that injecting a suspension of IFN-γ-secreting tumor cells results in their rejection. This effect has been attributed to IFN-γ preventing tumor stroma formation but not to a direct effect on the cancer cells. However, it is not known, which influence IFN-γ has on tumors with an established stroma. To address this question, the plasmacytoma cell line J558L was transduced with a vector allowing doxycycline-inducible IFN-γ gene expression. After the injection of the tumor cells into mice, IFN-γ was induced at different time points. Tumors did not grow when inducing IFN-γ immediately after tumor cell inoculation, while approximately half of the tumors were rejected when IFN-γ was induced in early established tumors within 2 weeks. Induction of IFN-γ 2-3 weeks after tumor cell inoculation was less efficient (0-17% rejection). IFN-γ induction in established tumors led to a reduction of CD146(+) endothelial cells and massive necrosis. Together, we show that vascularized tumors can be rejected by local IFN-γ expression, but that rejection of established tumors was less efficient over time. This suggests that transplanted tumors became less susceptible to local IFN-γ treatment the better they are established.
Assuntos
Interferon gama/biossíntese , Neoplasias Experimentais/imunologia , Animais , Rejeição de Enxerto , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Necrose , Transplante de Neoplasias , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/patologiaRESUMO
Adult hippocampal neurogenesis occurs in an exceptional permissive microenvironment. Neuroimmunological mechanisms might be prominently involved in the endogenous homeostatic principles that control baseline levels of adult neurogenesis. We show in this study that this homeostasis is partially dependent on CD4-positive T lymphocytes. Systemic depletion of CD4-positive T lymphocytes led to significantly reduced hippocampal neurogenesis, impaired reversal learning in the Morris water maze, and decreased brain-derived neurotrophic factor expression in the brain. No such effect of CD8 or B cells was observed. Repopulation of RAG2(-/-) mice with CD4, but not with CD8 cells again increased precursor cell proliferation. The T cells in our experiments were non-CNS specific and rarely detectable in the healthy brain. Thus, we can exclude cell-cell contacts between immune and brain cells or lymphocyte infiltration into the CNS as a prerequisite for an effect of CD4-T cells on neurogenesis. We propose that systemic CD4-T cell activity is required for maintaining cellular plasticity in the adult hippocampus and represents an evolutionary relevant communication route for the brain to respond to environmental changes.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Hipocampo/imunologia , Neurogênese/imunologia , Animais , Linfócitos B/imunologia , Proliferação de Células , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Imuno-Histoquímica , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subpopulações de Linfócitos T/imunologiaRESUMO
In the EU, the breeding of genetically modified laboratory animals is, by definition, an animal experiment if the offspring may experience pain, suffering, or harm. In order to determine the actual burden of genetically modified mice, established methods are available. However, the breeding of immunodeficient mice is considered an experiment requiring a permit, even if no pain, suffering or harm is observed under scientifically required defined hygienic housing conditions, as determined by established methods of severity assessment. This seems contradictory and leads to uncertainty among scientists. With this commentary, we would like to shed light on this topic from different perspectives and propose a solution in terms of individualized severity assessment and approval procedures.
RESUMO
The interactions between cancer and immune cells are complex. Even though the mutations that cause cancer can create new antigens that are potentially "visible" to T cells, in most experimental model systems the growth of tumors is accompanied by induction of T-cell tolerance towards the tumor. How tolerance to tumors is induced and how tolerance can be broken by immunotherapy have been a main focus in cancer immunology. Here, we discuss experimental models used in cancer immunology. We argue that, while it is obviously easy for tumors to induce tolerance, it should be as easy to circumvent tolerance by the adoptive transfer of tumor-antigen-reactive T cells. Effective adoptive T-cell therapy has become feasible by methods to identify TCR against tumor-associated (self-) antigens with high affinity and to graft a new antigen specificity to patients' T cells by TCR gene transfer.
Assuntos
Tolerância Imunológica/imunologia , Imunoterapia Adotiva , Neoplasias/terapia , Linfócitos T/imunologia , Linfócitos T/transplante , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Terapia Genética , Humanos , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
To understand the link between peripheral immune activation and neuronal precursor biology, we investigated the effect of T-cell activation on adult hippocampal neurogenesis in female C57Bl/6 mice. A peripheral adaptive immune response triggered by adjuvant-induced rheumatoid arthritis (2 microg/microl methylated BSA) or staphylococcus enterotoxin B (EC(50) of 0.25 microg/ml per 20 g body weight) was associated with a transient increase in hippocampal precursor cell proliferation and neurogenesis as assessed by immunohistochemistry and confocal microscopy. Both treatments were paralleled by an increase in corticosterone levels in the hippocampus 1- to 2-fold over the physiological amount measured by quantitative radioimmunoassay. In contrast, intraperitoneal administration of the innate immune response activator lipopolysaccaride (EC(50) of 0.5 microg/ml per 20 g body weight) led to a chronic 5-fold increase of hippocampal glucocorticoid levels and a decrease of adult neurogenesis. In vitro exposure of murine neuronal progenitor cells to corticosterone triggered either cell death at high (1.5 nM) or proliferation at low (0.25 nM) concentrations. This effect could be blocked using a viral vector system expressing a transdomain of the glucocorticoid receptor. We suggest an evolutionary relevant communication route for the brain to respond to environmental stressors like inflammation mediated by glucocorticoid levels in the hippocampus.
Assuntos
Proliferação de Células , Hipocampo/citologia , Imunidade , Neurônios/citologia , Células-Tronco/citologia , Animais , Artrite Experimental/imunologia , Feminino , Glucocorticoides/análise , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/imunologia , Linfócitos T/citologiaRESUMO
Tumor necrosis factor (TNF) was discovered in 1975 as a lipopolysaccharide-induced serum factor that causes necrosis of tumors (Carswell et al, 1975). It was later found that TNF and cachectin, a factor causing wasting disease, were one and the same molecule (Beutler et al, 1985). Studies on the inflammatory activity of TNF have been translated into clinical success, namely blocking antibodies used to suppress autoimmune diseases. Research on TNF anti-tumor activity, in contrast, has not yet resulted in a therapeutic breakthrough. This may change, based on a study by Huyghe et al (2020) describing novel "designer cytokines" (TNF and interferon-γ) that increase local activity by targeting the CD13-positive tumor vasculature, while simultaneously lowering the binding affinity to the respective cytokine receptor, thereby reducing off-target effects on normal cells.
Assuntos
Citocinas , Fator de Necrose Tumoral alfa , Imunoterapia , Interferon gama , LipopolissacarídeosRESUMO
Stressful experiences early in life can increase the risk of cardiovascular diseases. However, it remains largely unknown how stress influences susceptibility to the disease onset. Here, we show that exposure to brain-processed stress disrupts myocardial growth by reducing cardiomyocyte mitotic activity. Activation of the glucocorticoid receptor (GR), the primary stress response pathway, reduces cardiomyocyte numbers, disrupts trabecular formation, and leads to contractile dysfunction of the developing myocardium. However, a physiological level of GR signaling is required to prevent cardiomyocyte hyperproliferation. Mechanistically, we identify an antagonistic interaction between the GR and the cytokine interleukin-4 (IL-4) as a key player in cardiac development. IL-4 signals transcription of key regulators of cell-cycle progression in cardiomyocytes via signal transducer and activator of transcription 3 (Stat3). GR, on the contrary, inhibits this signaling system. Thus, our findings uncover an interplay between stress and immune signaling pathways critical to orchestrating physiological growth of the heart.
Assuntos
Interleucina-4 , Miócitos Cardíacos , Receptores de Glucocorticoides , Estresse Fisiológico , Animais , Feminino , Masculino , Camundongos , Glucocorticoides/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucina-4/fisiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitose , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Receptores de Glucocorticoides/imunologia , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/fisiologia , Fator de Transcrição STAT3/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismoRESUMO
It is controversially discussed whether immune-deficient mice experience severity in the absence of infection. Because a comprehensive analysis of the well-being of immune-deficient mice under specific pathogen free conditions is missing, we used a multi-parametric test analyzing, corticosterone, weight, nest building and facial expression over a period of 9 month to determine the well-being of two immune-deficient mouse lines (recombination activating gene 2- and interferon gamma receptor-deficient mice). We do not find evidence for severity when comparing immune-deficient mice to their heterozygous immune-competent littermates. Our data challenge the assumption that immune-deficiency per se regardless of housing conditions causes severity. Based on our study we propose to use objective non-invasive parameters determined by laboratory animal science for decisions concerning severity of immune-deficient mice.
Assuntos
Corticosterona/genética , Proteínas de Ligação a DNA/genética , Interferon gama/genética , Camundongos SCID/genética , Animais , Linfócitos B/imunologia , Corticosterona/imunologia , Humanos , Infecções/genética , Infecções/imunologia , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos SCID/imunologia , Dor/genética , Dor/patologia , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Transdução de Sinais/genética , Linfócitos T/imunologia , Testosterona/genética , Receptor de Interferon gamaRESUMO
Burnet postulated that the diversity of T-cell receptors (TCR) allows T cells to protect against the development of cancers that display antigens with a similar, seemingly endless diversity. To test this hypothesis, we developed a strategy in which a single breeding pair of mice gives rise to four groups of sibling mice. Three of the four groups had a similar number of CD8+ T cells, but TCR diversity was either broad, significantly reduced, or absent when expressing only one type of TCR. The fourth group had no T cells. All mice shared the same housing, and, therefore, their microbial environment was similar. Only slight differences in the intestinal flora were observed under these conditions. An undisturbed broad TCR repertoire was required for the rejection of inoculated cancers displaying the natural antigenic heterogeneity of primary tumors, whereas even one type of TCR was sufficient to protect against artificial cancers stably expressing cognate antigens. The three groups of mice with limited or no TCR repertoire showed an increased risk of developing primary tumors after chemical induction. However, the risk of early death or morbidity in these cohorts of mice was significantly higher than in mice with a diverse TCR repertoire, and it remains unknown whether mice with reduced TCR diversity, who died early without cancer, would have developed tumors with higher, lower, or equal probability after induction. Together, TCR diversity seems crucial to overcome the natural genetic instability of cancers and their antigenic heterogeneity, which impacts the design of cellular therapies.
Assuntos
Transplante de Neoplasias/métodos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/metabolismo , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genéticaRESUMO
In lymphopenic mice, T cells become activated and undergo lymphopenia-induced proliferation (LIP). However, not all T cells are equally sensitive to lymphopenia. Several lymphopenia-insensitive T cell clones were described and their non-responsiveness was mainly attributed to clone-specific properties. Here, we provide evidence for an additional, host-dependent mechanism restraining LIP of lymphopenia-insensitive CD4+ T cells. We show that such cells undergo LIP in lymphopenic mice lacking IFN-γ receptor (IFN-γR) expression, a process, which is promoted by the autocrine action of T cell-derived IFN-γ. Additionally, LIP of lymphopenia-insensitive CD4+ T cells requires an intact microflora and is accompanied by the massive accumulation of IL-6 and dendritic cells (DCs). Consistent with these results, IL-6 neutralization and the DC-specific restoration of IFN-γR expression are both sufficient to restrict LIP. Hence, the insensitivity of CD4+ T cells to lymphopenia relies on cell-intrinsic properties and a complex interplay between the commensal microflora, IL-6, IFN-γR+ DCs, and T cell-derived IFN-γ.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Linfopenia/imunologia , Receptores de Interferon/imunologia , Animais , Proliferação de Células , Doença Crônica , Interleucina-6/imunologia , Camundongos Transgênicos , Receptores de Interferon/genética , Transdução de Sinais , Receptor de Interferon gamaRESUMO
Excess salt intake could affect the immune system by shifting the immune cell balance toward a pro-inflammatory state. Since this shift of the immune balance is thought to be beneficial in anti-cancer immunity, we tested the impact of high salt diets on tumor growth in mice. Here we show that high salt significantly inhibited tumor growth in two independent murine tumor transplantation models. Although high salt fed tumor-bearing mice showed alterations in T cell populations, the effect seemed to be largely independent of adaptive immune cells. In contrast, depletion of myeloid-derived suppressor cells (MDSCs) significantly reverted the inhibitory effect on tumor growth. In line with this, high salt conditions almost completely blocked murine MDSC function in vitro. Importantly, similar effects were observed in human MDSCs isolated from cancer patients. Thus, high salt conditions seem to inhibit tumor growth by enabling more pronounced anti-tumor immunity through the functional modulation of MDSCs. Our findings might have critical relevance for cancer immunotherapy.
Assuntos
Imunidade , Neoplasias/imunologia , Neoplasias/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Animais , Apoptose , Biomarcadores , Modelos Animais de Doenças , Progressão da Doença , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/patologiaRESUMO
BACKGROUND: Neurotrophins have been implicated in the pathogenesis of asthma because of their ability to induce airway inflammation and to promote hyperreactivity of sensory neurons, which reflects an important mechanism in the pathogenesis of airway hyperreactivity. Neurotrophins use a dual-receptor system consisting of Trk-receptor tyrosine kinases and the structurally unrelated p75NTR. Previous studies revealed an important role of p75NTR in the pathogenesis of allergic asthma. OBJECTIVES: The aim of the study was to investigate the precise mechanisms of neurotrophins in neuroimmune interaction, which can lead to both airway inflammation and sensory nerve hyperreactivity in vivo. METHODS: Mice selectively expressing p75NTR in immune cells or nerves, respectively, were generated. After sensitization and allergen provocation, hyperreactivity of sensory nerves was tested in response to capsaicin. Airway inflammation was analyzed on the basis of differential cell counts and cytokine levels in bronchoalveolar lavage fluids. RESULTS: Allergic mice selectively expressing p75NTR in immune cells showed normal inflammation but no sensory nerve hyperreactivity, whereas mice selectively expressing p75NTR in nerve cells had a diminished inflammation and a distinct sensory nerve hyperreactivity. CONCLUSION: Our data indicate that p75NTR plays a dual role by promoting hyperreactivity of sensory nerves and airway inflammation. Additionally, our study provides experimental evidence that development of sensory nerve hyperreactivity depends on an established airway inflammation in asthma. In contrast, development of airway inflammation seems to be independent from sensory nerve hyperreactivity. CLINICAL IMPLICATIONS: Because of its dual function, antagonization of p75NTR-mediated signals might be a novel approach in asthma therapy.