RESUMEN
Eosinophilia is a hallmark characteristic of T helper type 2 (TH2) cell-associated diseases and is critically regulated by the central eosinophil growth factor interleukin 5 (IL-5). Here we demonstrate that IL-5 activity in eosinophils was regulated by paired immunoglobulin-like receptors PIR-A and PIR-B. Upon self-recognition of ß2-microglobulin (ß2M) molecules, PIR-B served as a permissive checkpoint for IL-5-induced development of eosinophils by suppressing the proapoptotic activities of PIR-A, which were mediated by the Grb2-Erk-Bim pathway. PIR-B-deficient bone marrow eosinophils underwent compartmentalized apoptosis, resulting in decreased blood eosinophilia in naive mice and in mice challenged with IL-5. Subsequently, Pirb(-/-) mice displayed impaired aeroallergen-induced lung eosinophilia and induction of lung TH2 cell responses. Collectively, these data uncover an intrinsic, self-limiting pathway regulating IL-5-induced expansion of eosinophils, which has broad implications for eosinophil-associated diseases.
Asunto(s)
Diferenciación Celular/inmunología , Eosinófilos/inmunología , Interleucina-5/inmunología , Receptores Inmunológicos/inmunología , Animales , Apoptosis/genética , Apoptosis/inmunología , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas Reguladoras de la Apoptosis/metabolismo , Asma/genética , Asma/inmunología , Asma/metabolismo , Proteína 11 Similar a Bcl2 , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias/métodos , Eosinófilos/citología , Eosinófilos/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Citometría de Flujo , Proteína Adaptadora GRB2/genética , Proteína Adaptadora GRB2/inmunología , Proteína Adaptadora GRB2/metabolismo , Expresión Génica/inmunología , Interleucina-5/farmacología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/inmunología , Proteínas Proto-Oncogénicas/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transducción de Señal/inmunología , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/inmunologíaRESUMEN
IL-4 receptor (R) α, the common receptor chain for IL-4 and IL-13, is a critical component in IL-4- and IL-13-mediated signaling and subsequent effector functions such as those observed in type 2 inflammatory responses. Nonetheless, the existence of intrinsic pathways capable of amplifying IL-4Rα-induced responses remains unknown. In this study, we identified the myeloid-associated Ig receptor CD300f as an IL-4-induced molecule in macrophages. Subsequent analyses demonstrated that CD300f was colocalized and physically associated with IL-4Rα. Using Cd300f(-/-) cells and receptor cross-linking experiments, we established that CD300f amplified IL-4Rα-induced responses by augmenting IL-4/IL-13-induced signaling, mediator release, and priming. Consistently, IL-4- and aeroallergen-treated Cd300f(-/-) mice displayed decreased IgE production, chemokine expression, and inflammatory cell recruitment. Impaired responses in Cd300f(-/-) mice were not due to the inability to generate a proper Th2 response, because IL-4/IL-13 levels were markedly increased in allergen-challenged Cd300f(-/-) mice, a finding that is consistent with decreased cytokine consumption. Finally, CD300f expression was increased in monocytes and eosinophils obtained from allergic rhinitis patients. Collectively, our data highlight a previously unidentified role for CD300f in IL-4Rα-induced immune cell responses. These data provide new insights into the molecular mechanisms governing IL-4Rα-induced responses, and may provide new therapeutic tools to target IL-4 in allergy and asthma.
Asunto(s)
Sistema Inmunológico/inmunología , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Interleucina-4/fisiología , Receptores Inmunológicos/metabolismo , Alérgenos/inmunología , Animales , Sistema Inmunológico/citología , Inmunoglobulina E/biosíntesis , Activación de Macrófagos/fisiología , Ratones , Ratones Noqueados , Unión Proteica , Receptores Inmunológicos/genética , Receptores Inmunológicos/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND: The exposure of blood to the artificial circuit during extracorporeal membrane oxygenation (ECMO) can induce an inflammatory response. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation. METHODS: In this retrospective observational study, we analyzed results of daily plasma CRP measurements in 110 critically ill patients, treated with ECMO. We compared CRP levels during the first 5 days of ECMO operation, between different groups of patients according to ECMO configurations, Coronavirus disease 2019 (COVID-19) status, and mechanical ventilation parameters. RESULTS: There was a statistically significant decrease in CRP levels during the first 5 days of veno-venous (VV) ECMO (173 ± 111 mg/L, 154 ± 107 mg/L, 127 ± 97 mg/L, 114 ± 100 mg/L and 118 ± 90 mg/L for days 1-5 respectively, p < 0.001). Simultaneously, there was a significant reduction in ventilatory parameters, as represented by the mechanical power (MP) calculation, from 24.02 ± 14.53 J/min to 6.18 ± 4.22 J/min within 3 h of VV ECMO initiation (p < 0.001). There was non-significant trend of increase in CRP level during the first 5 days of veno arterial (VA) ECMO (123 ± 80 mg/L, 179 ± 91 mg/L, 203 ± 90 mg/L, 179 ± 95 mg/L and 198 ± 93 for days 1-5 respectively, p = 0.126) and no significant change in calculated MP (from 14.28 ± 8.56 J/min to 10.81 ± 8.09 J/min within 3 h if ECMO initiation, p = 0.071). CONCLUSIONS: We observed a significant decrease in CRP levels during the first 5 days of VV ECMO support, and suggest that the concomitant reduction in ventilatory MP may have mitigated the degree of alveolar stress and strain that could have contributed to a decrease in the systemic inflammatory process.
Asunto(s)
COVID-19 , Oxigenación por Membrana Extracorpórea , Humanos , Oxigenación por Membrana Extracorpórea/efectos adversos , Oxigenación por Membrana Extracorpórea/métodos , Proteína C-Reactiva , Inflamación/etiología , Estudios RetrospectivosRESUMEN
OBJECTIVE: Mean arterial pressure (MAP) plays a significant role in regulating tissue perfusion and urine output (UO). The optimal MAP target in critically ill patients remains a subject of debate. We aimed to explore the relationship between MAP and UO. DESIGN: A retrospective observational study. SETTING: A general ICU in a tertiary medical center. PATIENTS: All critically ill patients admitted to the ICU for more than 10 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: MAP values and hourly UO were collected in 5,207 patients. MAP levels were categorized into 10 groups of 5 mm Hg (from MAP < 60 mm Hg to MAP > 100 mg Hg), and 656,423 coupled hourly mean MAP and UO measurements were analyzed. Additionally, we compared the UO of individual patients in each MAP group with or without norepinephrine (NE) support or diuretics, as well as in patients with acute kidney injury (AKI).Hourly UO rose incrementally between MAP values of 65-100 mm Hg. Among 2,226 patients treated with NE infusion, mean UO was significantly lower in the MAP less than 60 mm Hg group (53.4 mL/hr; 95% CI, 49.3-57.5) compared with all other groups (p < 0.001), but no differences were found between groups of 75 less than or equal to MAP. Among 2500 patients with AKI, there was a linear increase in average UO from the MAP less than 60 mm Hg group (57.1 mL/hr; 95% CI, 54.2-60.0) to the group with MAP greater than or equal to 100 mm Hg (89.4 mL/hr; 95% CI, 85.7-93.1). When MAP was greater than or equal to 65 mm Hg, we observed a statistically significant trend of increased UO in periods without NE infusion. CONCLUSIONS: Our analysis revealed a linear correlation between MAP and UO within the range of 65-100 mm Hg, also observed in the subgroup of patients treated with NE or diuretics and in those with AKI. These findings highlight the importance of tissue perfusion to the maintenance of diuresis and achieving adequate fluid balance in critically ill patients.
Asunto(s)
Presión Arterial , Enfermedad Crítica , Unidades de Cuidados Intensivos , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Presión Arterial/efectos de los fármacos , Presión Arterial/fisiología , Anciano , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/orina , Lesión Renal Aguda/diagnóstico , Norepinefrina/orina , Micción/efectos de los fármacos , Micción/fisiologíaRESUMEN
Macrophages are lung-resident cells that play key roles in fibrosis. Surprisingly, pathways that inhibit macrophage functions, especially in idiopathic pulmonary fibrosis (IPF), receive little attention. The cell-surface molecule paired immunoglobulin-like receptor B (PIR-B) can suppress macrophage activation. However, its role in pulmonary fibrosis remains unknown. We sought to define the role of PIR-B in IPF. The expression of PIR-B was assessed (by quantitative PCR and flow cytometry) after bleomycin treatment. Differential cell counts, histopathology, and profibrogenic-mediator expression, for example, collagen, α-smooth muscle actin, resistin-like molecule-α (Relm-α), matrix metalloproteinase (MMP)-12, and tissue inhibitor of metalloproteinase (TIMP)-1, were determined (by ELISA quantitative PCR and flow cytometry) in the lungs of wild-type and Pirb(-/-) mice after bleomycin or IL-4 treatment. Bone marrow-derived wild-type and Pirb(-/-) macrophages were stimulated with IL-4 and assessed for Relm-α and MMP-12 expression. PIR-B was up-regulated in lung myeloid cells after bleomycin administration. Bleomycin-treated Pirb(-/-) mice displayed increased lung histopathology and an increased expression of collagen and of the IL-4-associated profibrogenic markers Relm-α, MMP-12, TIMP-1, and osteopontin, which were localized to alveolar macrophages. Increased profibrogenic mediator expression in Pirb(-/-) mice was not attributable to increased IL-4/IL-13 concentrations, suggesting that PIR-B negatively regulates IL-4-induced macrophage activation. Indeed, IL-4-treated Pirb(-/-) mice displayed increased Relm-α expression and Relm-α(+) macrophage concentrations. IL-4-activated Pirb(-/-) macrophages displayed increased Relm-α and MMP-12 induction. Finally, leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3)/immunoglobulin-like transcript-5, the human PIR-B orthologue, was expressed and up-regulated in lung biopsies from patients with IPF. Our results establish a key role for PIR-B in IPF, likely via the regulation of macrophage activation. Therefore, PIR-B/LILRB3 may offer a possible target for suppressing macrophage profibrogenic activity in IPF.
Asunto(s)
Activación de Macrófagos , Macrófagos Alveolares/metabolismo , Fibrosis Pulmonar/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Antibióticos Antineoplásicos/farmacología , Bleomicina/efectos adversos , Bleomicina/farmacología , Humanos , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/genética , Interleucina-4/farmacología , Macrófagos Alveolares/patología , Metaloproteinasa 12 de la Matriz/biosíntesis , Metaloproteinasa 12 de la Matriz/genética , Ratones , Ratones Noqueados , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Receptores Inmunológicos/genética , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: CCAAT/enhancer-binding protein ß (C/EBPß) is a transcription factor known to be involved in macrophage differentiation and function, steatohepatitis and liver fibrosis. METHODS: Immune restricted C/EBPß deficient and control mice were investigated in steady-state and in the CDA-HFD steatohepatitis model. Mice were assessed for weight change, liver biochemical profile, histology and hepatic phagocytes composition. RESULTS: Flow cytometry analysis of hepatic nonparenchymal cells revealed reduced numbers of hepatic monocytes and Kupffer cells and an increase in hepatic MHC class II positive myeloid cells in immune cells restricted C/EBPß deficient mice. Immune-restricted C/EBPß deficiency resulted in decreased weight gain and appearance of mild spontaneous liver inflammation. Nevertheless, In the CDA-HFD steatohepatitis model, immune restricted C/EBPß deficient and proficient mice exhibit similar grade of hepatic steatosis, liver enzymes levels and fibrosis stage. CONCLUSIONS: Immune-restricted C/EBPß deficiency leads to significant alteration in hepatic mononuclear phagocytes composition associated with spontaneous mild hepatitis. Steatohepatitis associated fibrosis is not dependent on C/EBPß expression by immune cells.
Asunto(s)
Hígado Graso , Hepatitis , Ratones , Animales , Hígado Graso/complicaciones , Cirrosis Hepática/complicaciones , Hepatitis/complicaciones , Regulación de la Expresión GénicaRESUMEN
Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6Chi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6Chi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos del Hígado/metabolismo , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Diferenciación Celular/genética , Supervivencia Celular , Hematopoyesis , Inflamasomas/metabolismo , Inflamación/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Macrófagos del Hígado/fisiología , Hígado/citología , Hígado/lesiones , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismoRESUMEN
The CD300 family of receptors is an evolutionary conserved receptor family that belongs to the Ig superfamily and is expressed predominantly by the myeloid lineage. Over the past couple of years, accumulating data have shown that eosinophils express various Ig superfamily receptors that regulate key checkpoints in their biology including their maturation, transition from the bone marrow to the peripheral blood, migration, adhesion, survival, and effector functions in response to numerous activating signals such as IL-4, IL-33, and bacteria. In this review, we will present the emerging roles of CD300 family receptors and specifically CD300a and CD300f in the regulation of these eosinophil activities. The structure and expression pattern of these molecules will be discussed and their involvement in suppressing or co-activating eosinophil functions in health and disease will be illustrated.
Asunto(s)
Antígenos CD/metabolismo , Eosinófilos/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Supervivencia Celular/fisiología , Quimiotaxis de Leucocito/fisiología , HumanosRESUMEN
The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6Chi monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C-C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in amelioration of all aspects of disease severity including serum total bile acids, histological severity score, and fibrosis stage. In conclusion, our results indicate a major role for Ly6Chi monocytes and for CCR2 in PBC pathogenesis and suggest that inhibition of this axis by CVC should be explored in humans through the use of clinical trials.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Colangitis/inmunología , Colangitis/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Receptores CCR2/metabolismo , Animales , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/patología , Biomarcadores , Quimiocinas/metabolismo , Colangitis/complicaciones , Colangitis/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Imidazoles/farmacología , Cirrosis Hepática/etiología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Monocitos/efectos de los fármacos , Receptores CCR2/antagonistas & inhibidores , Receptores CCR2/genética , Sulfóxidos , Células THP-1RESUMEN
The function of NCR1 was studied in a model of experimental asthma, classified as a type 1 hypersensitivity reaction, in mice. IgE levels were significantly increased in the serum of OVA immunized NCR1 deficient (NCR1gfp/gfp) mice in comparison to OVA immunized wild type (NCR1+/+) and adjuvant immunized mice. Histological analysis of OVA immunized NCR1gfp/gfp mice revealed no preservation of the lung structure and overwhelming peribronchial and perivascular granulocytes together with mononuclear cells infiltration. OVA immunized NCR+/+ mice demonstrated preserved lung structure and peribronchial and perivascular immune cell infiltration to a lower extent than that in NCR1gfp/gfp mice. Adjuvant immunized mice demonstrated lung structure preservation and no immune cell infiltration. OVA immunization caused an increase in PAS production independently of NCR1 presence. Bronchoalveolar lavage (BAL) revealed NCR1 dependent decreased percentages of eosinophils and increased percentages of lymphocytes and macrophages following OVA immunization. In the OVA immunized NCR1gfp/gfp mice the protein levels of eosinophils' (CCL24) and Th2 CD4+ T-cells' chemoattractants (CCL17, and CCL24) in the BAL are increased in comparison with OVA immunized NCR+/+ mice. In the presence of NCR1, OVA immunization caused an increase in NK cells numbers and decreased NCR1 ligand expression on CD11c+GR1+ cells and decreased NCR1 mRNA expression in the BAL. OVA immunization resulted in significantly increased IL-13, IL-4 and CCL17 mRNA expression in NCR1+/+ and NCR1gfp/gfp mice. IL-17 and TNFα expression increased only in OVA-immunized NCR1+/+mice. IL-6 mRNA increased only in OVA immunized NCR1gfp/gfp mice. Collectively, it is demonstrated that NCR1 dampens allergic eosinophilic airway inflammation.