RESUMEN
CCR2 is the major chemokine receptor that regulates appropriate trafficking of inflammatory monocytes, but the role of this chemokine receptor and its ligands during primary and secondary infection with intracellular infections remains incompletely understood. Here we used murine infection with the Live Vaccine Strain (LVS) of Francisella tularensis to evaluate the role of CCR2 during primary and secondary parenteral responses to this prototype intracellular bacterium. We find that mice deficient in CCR2 are highly compromised in their ability to survive intradermal infection with LVS, indicating the importance of this receptor during primary parenteral responses. Interestingly, this defect could not be readily attributed to the activities of the known murine CCR2 ligands MCP-1/CCL2, MCP-3/CCL7, or MCP-5/CCL12. Nonetheless, CCR2 knockout mice vaccinated by infection with low doses of LVS generated optimal T cell responses that controlled the intramacrophage replication of Francisella, and LVS-immune CCR2 knockout mice survived maximal lethal Francisella challenge. Thus, fully protective adaptive immune memory responses to this intracellular bacterium can be readily generated in the absence of CCR2.
Asunto(s)
Francisella tularensis/fisiología , Receptores CCR2/genética , Tularemia/inmunología , Animales , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/inmunología , Quimiocina CCL2/deficiencia , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL7/deficiencia , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Francisella tularensis/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/citología , Monocitos/metabolismo , Receptores CCR2/deficiencia , Tasa de Supervivencia , Linfocitos T/inmunología , Linfocitos T/metabolismo , Tularemia/mortalidad , Tularemia/patología , Tularemia/prevención & control , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunologíaRESUMEN
Acute kidney injury (AKI) is a serious condition affecting one fifth of hospital inpatients. B lymphocytes have immunological functions beyond Ab production and may produce cytokines and chemokines that modulate inflammation. In this study, we investigated leukocyte responses in a mouse model of AKI and observed an increase in circulating and kidney B cells, particularly a B220low subset, following AKI. We found that B cells produce the chemokine CCL7, with the potential to facilitate neutrophil and monocyte recruitment to the injured kidney. Siglec-G-deficient mice, which have increased numbers of B220low innate B cells and a lower B cell activation threshold, had increased Ccl7 transcripts, increased neutrophil and monocyte numbers in the kidney, and more severe AKI. CCL7 blockade in mice reduced myeloid cell infiltration into the kidney and ameliorated AKI. In two independent cohorts of human patients with AKI, we observed significantly higher CCL7 transcripts compared with controls, and in a third cohort, we observed an increase in urinary CCL7 levels in AKI, supporting the clinical importance of this pathway. Together, our data suggest that B cells contribute to early sterile inflammation in AKI via the production of leukocyte-recruiting chemokines.
Asunto(s)
Lesión Renal Aguda/inmunología , Linfocitos B/inmunología , Quimiocina CCL7/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Animales , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Inflamación/inmunología , Riñón/inmunología , Leucocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
Compelling evidence has demonstrated that Th17 cells play an essential role in the pathogenesis of multiple sclerosis (MS). Long noncoding RNAs (lncRNAs) have been confirmed as vital regulators of immune cell differentiation and other functions. However, whether and how lncRNAs influence Th17 cell differentiation and functional behaviors remain largely unclear. Here, we identified that a lncRNA, namely Gm15575, is specifically enriched in Th17 cells and spleen tissues of EAE mice. Functionally, knockdown of Gm15575 in Th17 cells suppressed the secretion of IL17A. Mechanistically, Gm15575 served as a competing endogenous RNA (ceRNA) to block the function of miR-686, positively regulating the expression of CCL7, a pro-inflammatory chemokine with high expression in Th17 cells, and Th17 differentiation. Taken together, our study revealed that Gm15575-miR-686 axis promoted the progression of EAE by regulating Th17 differentiation and expression of CCL7 which elucidated the pathogenesis of autoimmune diseases at genetic level. Gm15575 can be involved in the course of Th17-related autoimmune diseases.
Asunto(s)
Quimiocina CCL7/biosíntesis , Encefalomielitis Autoinmune Experimental/genética , Regulación de la Expresión Génica/inmunología , MicroARNs/genética , ARN Largo no Codificante/genética , Células Th17/inmunología , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Ratones , MicroARNs/inmunología , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , ARN Largo no Codificante/inmunología , Regulación hacia ArribaRESUMEN
The tumor microenvironment is the primary location in which tumor cells and the host immune system interact. There are many physiological, biochemical, cellular mechanisms in the neighbor of tumor which is composed of various cell types. Interactions of chemokines and chemokine receptors can recruit immune cell subsets into the tumor microenvironment. These interactions can modulate tumor progression and metastasis. In this chapter, we will focus on chemokine (C-C motif) ligand 7 (CCL7) that is highly expressed in the tumor microenvironment of various cancers, including colorectal cancer, breast cancer, oral cancer, renal cancer, and gastric cancer. We reviewed how CCL7 can affect cancer immunity and tumorigenesis by describing its regulation and roles in immune cell recruitment and stromal cell biology.
Asunto(s)
Quimiocina CCL7/inmunología , Transducción de Señal/inmunología , Microambiente Tumoral/inmunología , Animales , Carcinogénesis/inmunología , Humanos , Receptores de Quimiocina/metabolismoRESUMEN
Background: Macrophages are pivotal in coordinating a range of important processes in the intestines, including controlling intracellular infections and limiting damaging inflammation against the microbiota. However, it is not clear how gut macrophages, relative to recruited blood monocytes and other myeloid cells, contribute to the intestinal inflammatory milieu, nor how macrophages and their monocyte precursors mediate recruitment of other immune cells to the inflamed intestine. Methods: Myeloid cell populations isolated from colonic inflammatory bowel disease (IBD) or murine dextran sulphate sodium (DSS) induced colitis were assessed using flow cytometry and compared to healthy controls. In addition, mRNA expression profiles in human and murine colon samples, and in macrophages and monocytes from healthy and inflamed murine colons, were analysed by quantitative PCR (qPCR) and mRNA microarray. Results: We show that the monocyte:macrophage balance is disrupted in colon inflammation to favour recruitment of CD14+HLA-DRInt cells in humans, and Ly6CHi monocytes in mice. In addition, we identify that murine blood monocytes receive systemic signals enabling increased release of IL-1ß prior to egress from the blood into the colon. Further, once within the colon and relative to other myeloid cells, monocytes represent the dominant local source of both IL-1ß and TNF. Finally, our data reveal that, independent of inflammation, murine colon macrophages act as a major source of Ccl7 and Ccl8 chemokines that trigger further recruitment of their pro-inflammatory monocyte precursors. Conclusions: Our work suggests that strategies targeting macrophage-mediated monocyte recruitment may represent a promising approach for limiting the chronic inflammation that characterises IBD.
Asunto(s)
Colitis/inmunología , Colon/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Animales , Quimiocina CCL7/inmunología , Quimiocina CCL8/inmunología , Sulfato de Dextran/inmunología , Femenino , Humanos , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-1beta/inmunología , Ratones , Ratones Endogámicos C57BL , Factores de Necrosis Tumoral/inmunologíaRESUMEN
The chemokine CCL7 (MCP3) is known to promote the recruitment of many innate immune cell types including monocytes and neutrophils to sites of bacterial and viral infection and eosinophils and basophils to sites of allergic inflammation. CCL7 upregulation has been associated with many inflammatory settings including infection, cardiovascular disease, and the tumor microenvironment. CCL7's pleotropic effects are due in part to its ability to bind numerous chemokine receptors, namely CCR1, CCR2, CCR3, CCR5, and CCR10. CCL7-blockade or CCL7-deficiency is often marked by decreased inflammation and poor pathogen control. In the context of Leishmania major infection, CCL7 is specifically upregulated in the skin one-2 weeks after infection but its role in L. major control is unclear. To determine CCL7's impact on the response to L. major we infected WT and CCL7-/- C57BL/6 mice. L. major infection of CCL7-deficient mice led to an unexpected increase in inflammation in the infected skin 2 weeks post-infection. A broad increase in immune cell subsets was observed but was dominated by enhanced neutrophilic infiltration. Increased neutrophil recruitment was associated with an enhanced IL-17 gene profile in the infected skin. CCL7 was shown to directly antagonize neutrophil migration in vitro and CCL7 add-back in vivo specifically reduced neutrophil influx into the infected skin revealing an unexpected role for CCL7 in limiting neutrophil recruitment during L. major infection. Enhanced neutrophilic infiltration in CCL7-deficient mice changed the balance of L. major infected host cells with an increase in the ratio of infected neutrophils over monocytes/macrophages. To determine the consequence of CCL7 deficiency on L. major control we analyzed parasite load cutaneously at the site of infection and viscerally in the draining LN and spleen. The CCL7-/- mice supported robust cutaneous parasite control similar to their WT C57BL/6 counterparts. In contrast, CCL7-deficiency led to greater parasite dissemination and poor parasite control in the spleen. Our studies reveal a novel role for CCL7 in negatively regulating cutaneous inflammation, specifically neutrophils, early during L. major infection. We propose that CCL7-mediated dampening of the early immune response in the skin may limit the ability of the parasite to disseminate without compromising cutaneous control.
Asunto(s)
Quimiocina CCL7/inmunología , Quimiocina CCL7/metabolismo , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Análisis de Varianza , Animales , Movimiento Celular , Quimiocina CCL7/genética , Quimiocina CXCL2/metabolismo , Expresión Génica , Inflamación/genética , Inflamación/inmunología , Interleucina-17/genética , Leishmaniasis Cutánea/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/inmunología , Neutrófilos/fisiología , Estadísticas no ParamétricasRESUMEN
We previously found CC chemokine ligand 3 (CCL3) to be a potent effector of inflammation during otitis media (OM): exogenous CCL3 rescues the OM phenotype of tumor necrosis factor-deficient mice and the function of macrophages deficient in several innate immune molecules. To further delineate the role of CCL3 in OM, we evaluated middle ear (ME) responses of ccl3-/-mice to nontypeable Haemophilus influenzae (NTHi). CCL chemokine gene expression was evaluated in wild-type (WT) mice during the complete course of acute OM. OM was induced in ccl3-/- and WT mice, and infection and inflammation were monitored for 21 days. Phagocytosis and killing of NTHi by macrophages were evaluated by an in vitro assay. The nasopharyngeal bacterial load was assessed in naive animals of both strains. Many CCL genes showed increased expression levels during acute OM, with CCL3 being the most upregulated, at levels 600-fold higher than the baseline. ccl3-/- deletion compromised ME bacterial clearance and prolonged mucosal hyperplasia. ME recruitment of leukocytes was delayed but persisted far longer than in WT mice. These events were linked to a decrease in the macrophage capacity for NTHi phagocytosis and increased nasopharyngeal bacterial loads in ccl3-/- mice. The generalized impairment in inflammatory cell recruitment was associated with compensatory changes in the expression profiles of CCL2, CCL7, and CCL12. CCL3 plays a significant role in the clearance of infection and resolution of inflammation and contributes to mucosal host defense of the nasopharyngeal niche, a reservoir for ME and upper respiratory infections. Therapies based on CCL3 could prove useful in treating or preventing persistent disease.
Asunto(s)
Quimiocina CCL3/inmunología , Oído Medio/inmunología , Infecciones por Haemophilus/inmunología , Haemophilus influenzae/inmunología , Nasofaringe/inmunología , Otitis Media/inmunología , Animales , Carga Bacteriana , Movimiento Celular , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL3/deficiencia , Quimiocina CCL3/genética , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Modelos Animales de Enfermedad , Oído Medio/microbiología , Regulación de la Expresión Génica , Infecciones por Haemophilus/genética , Infecciones por Haemophilus/microbiología , Infecciones por Haemophilus/patología , Interacciones Huésped-Patógeno , Leucocitos/inmunología , Leucocitos/microbiología , Macrófagos/inmunología , Macrófagos/microbiología , Ratones , Ratones Noqueados , Proteínas Quimioatrayentes de Monocitos/genética , Proteínas Quimioatrayentes de Monocitos/inmunología , Nasofaringe/microbiología , Otitis Media/genética , Otitis Media/microbiología , Otitis Media/patología , Fagocitosis , Transducción de SeñalRESUMEN
Molecules that are necessary for ocular hypersensitivity reactions include the receptors CCR1 and CCR3; CCL7 is a ligand for these receptors. Therefore, we explored the role of CCL7 in mast cell activity and motility in vitro and investigated the requirement for CCL7 in a murine model of IgE-mediated allergic conjunctivitis. For mast cells treated with IgE and Ag, the presence of CCL7 synergistically enhanced degranulation and calcium influx. CCL7 also induced chemotaxis in mast cells. CCL7-deficient bone marrow-derived mast cells showed decreased degranulation following IgE and Ag treatment compared with wild-type bone marrow-derived mast cells, but there was no difference in degranulation when cells were activated via an IgE-independent pathway. In vivo, CCL7 was upregulated in conjunctival tissue during an OVA-induced allergic response. Notably, the early-phase clinical symptoms in the conjunctiva after OVA challenge were significantly higher in OVA-sensitized wild-type mice than in control challenged wild-type mice; the increase was suppressed in CCL7-deficient mice. In the OVA-induced allergic response, the numbers of conjunctival mast cells were lower in CCL7-deficient mice than in wild-type mice. Our results demonstrate that CCL7 is required for maximal OVA-induced ocular anaphylaxis, mast cell recruitment in vivo, and maximal FcεRI-mediated mast cell activation in vitro. A better understanding of the role of CCL7 in mediating ocular hypersensitivity reactions will provide insights into mast cell function and novel treatments for allergic ocular diseases.
Asunto(s)
Quimiocina CCL7/inmunología , Conjuntivitis Alérgica/inmunología , Mastocitos/inmunología , Animales , Western Blotting , Degranulación de la Célula/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
End-stage renal disease (ESRD) patients exhibit elevated risk of tuberculosis (TB) reactivation, but current diagnostics, including the interferon gamma release assay (IGRA), exhibit poor sensitivity in ESRD. We tested 80 ESRD patients and found an 18.75% prevalence of IGRA positivity. A subset of patients was assessed for Mtb-specific expression of 44 cytokines/chemokines, and CD4+ T cell phenotype and function. Similar to non-ESRD IGRA+ individuals, Mtb-specific IFNγ, IL-1RA, IP-10, MCP-3 and IL-2 responses were identified in the ESRD IGRA+ group. 27% of the ESRD IGRA- group exhibited MCP-3 or IL-2 Mtb-specific responses, which may identify cases of latent TB infection in ESRD. Stimulation of PBMC with PPD demonstrated similar CD4+ T cell production of IFNγ, TNFα and GM-CSF by ESRD patients. The reported low sensitivity of the IGRA in ESRD cohorts is therefore unlikely to be due to poor T cell cytokine secretion, and may instead reflect defects in antigen presentation.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Fallo Renal Crónico/inmunología , Tuberculosis Latente/inmunología , Mycobacterium tuberculosis/inmunología , Anciano , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Quimiocina CCL7/inmunología , Quimiocina CCL7/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Citometría de Flujo , Interacciones Huésped-Patógeno/inmunología , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Fallo Renal Crónico/metabolismo , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/microbiología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/fisiología , Curva ROCAsunto(s)
Citocinas/genética , Enteritis/genética , Eosinofilia/genética , Eosinófilos/inmunología , Gastritis/genética , Interleucina-33/genética , Estudios de Casos y Controles , Quimiocina CCL21/sangre , Quimiocina CCL21/genética , Quimiocina CCL21/inmunología , Quimiocina CCL27/sangre , Quimiocina CCL27/genética , Quimiocina CCL27/inmunología , Quimiocina CCL7/sangre , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Citocinas/sangre , Citocinas/inmunología , Enteritis/sangre , Enteritis/inmunología , Enteritis/patología , Eosinofilia/sangre , Eosinofilia/inmunología , Eosinofilia/patología , Eosinófilos/patología , Femenino , Gastritis/sangre , Gastritis/inmunología , Gastritis/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Lactante , Interleucina-33/sangre , Interleucina-33/inmunología , Masculino , Linfopoyetina del Estroma TímicoRESUMEN
Recent studies show that methamphetamine (Meth) use leads to higher susceptibility to and progression of infections, which suggests impairment of the immune system. The first line of defense against infections is the innate immune system and the macrophage is a key player in preventing and fighting infections. So we profiled cytokines over time in Meth treated THP-1 cells, as a human macrophage model, at a relevant concentration using high throughput screening to find a signaling target. We showed that after a single exposure, the effect of Meth on macrophage cytokine production was rapid and time dependent and shifted the balance of expression of cytokines to pro-inflammatory. Our results were analogous to previous reports in that Meth up-regulates TNF-α and IL-8 after two hours of exposure. However, global screening led to the novel identification of CXCL16, CXCL1 and many other up-regulated cytokines. We also showed CCL7 as the most down-regulated chemokine due to Meth exposure, which led us to hypothesize that Meth dysregulates the MyD88-dependent Toll-like receptor 9 (TLR9) signaling pathway. In conclusion, altered cytokine expression in macrophages suggests it could lead to a suppressed innate immunity in people who use Meth.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Macrófagos/efectos de los fármacos , Metanfetamina/farmacología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 9/genética , Línea Celular , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Quimiocina CXCL16 , Quimiocinas CXC/genética , Quimiocinas CXC/inmunología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Interleucina-8/genética , Interleucina-8/inmunología , Macrófagos/citología , Macrófagos/inmunología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Receptores Depuradores/genética , Receptores Depuradores/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 9/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The omental fat band (OFB) is the predominant site for metastatic seeding of ovarian cancer. Previously, we highlighted the influx and accumulation of neutrophils and macrophages in the OFB following syngeneic ovarian cancer cell seeding as an important factor in the development of a protumorigenic cascade. Here we investigated localized immunomodulation as a means of promoting a successful protective response. As an important TH1-type immunomodulator, interleukin (IL)-12 has previously been investigated clinically as an anticancer therapeutic. However, systemic IL-12 administration was associated with serious side effects, galvanizing the development of immune or accessory cells engineered to express secreted or membrane-bound IL-12 (mbIL-12). Using an mbIL-12-expressing cell variant, we demonstrate that localized IL-12 in the tumor microenvironment significantly delays disease development. The mbIL-12-mediated decrease in tumor burden was associated with a significant reduction in neutrophil and macrophage infiltration in the OFB, and correlated with a reduced expression of neutrophil and macrophage chemoattractants (CXCL1, -2, -3 and CCL2, -7). Vaccination with mitotically impaired tumor cells did not confer protection against subsequent tumor challenge, indicating that IL-12 did not impact the immunogenicity of the cancer cells. Our findings are in agreement with previous reports suggesting that IL-12 may hold promise when delivered in a targeted and sustained manner to the omental microenvironment. Furthermore, resident cells within the omental microenvironment may provide a reservoir that can be activated and mobilized to prevent metastatic seeding within the peritoneum and, therefore, may be targets for chemotherapeutics.
Asunto(s)
Carcinogénesis/inmunología , Inmunomodulación/genética , Interleucina-12/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Peritoneales/inmunología , Microambiente Tumoral/inmunología , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Quimiocina CXCL2/genética , Quimiocina CXCL2/inmunología , Quimiocinas CXC/genética , Quimiocinas CXC/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Interleucina-12/genética , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/patología , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Neutrófilos/inmunología , Neutrófilos/patología , Epiplón/inmunología , Epiplón/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ovario/inmunología , Ovario/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Transducción de Señal , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is characterized by lung and systemic inflammation as well as airway goblet cell hyperplasia (GCH). Mucin production is activated in part by stimulation of the epidermal growth factor (EGF) receptor pathway through neutrophils and macrophages. How circulating cytokine levels relate to GCH is not clear. METHODS: We performed phlebotomy and bronchoscopy on 25 subjects (six nonsmokers, 11 healthy smokers, and eight COPD subjects FEV1 30-60 %). Six endobronchial biopsies per subject were performed. GCH was measured by measuring mucin volume density (MVD) using stereological techniques on periodic acid fast-Schiff stained samples. We measured the levels of chemokines CXCL8/IL-8, CCL2/MCP-1, CCL7/MCP-3, CCL22/MCD, CCL3/MIP-1α, and CCL4/MIP-1ß, and the cytokines IL-1, IL-4, IL-6, IL-9, IL-17, EGF, and vascular endothelial growth factor (VEGF). Differences between groups were assessed using one-way ANOVA, t test, or Chi squared test. Post hoc tests after ANOVA were performed using Bonferroni correction. RESULTS: MVD was highest in healthy smokers (27.78 ± 10.24 µL/mm(2)) compared to COPD subjects (16.82 ± 16.29 µL/mm(2), p = 0.216) and nonsmokers (3.42 ± 3.07 µL/mm(2), p < 0.0001). Plasma CXCL8 was highest in healthy smokers (11.05 ± 8.92 pg/mL) compared to nonsmokers (1.20 ± 21.92 pg/mL, p = 0.047) and COPD subjects (6.01 ± 5.90 pg/mL, p = 0.366). CCL22 and CCL4 followed the same trends. There were no significant differences in the other cytokines measured. When the subjects were divided into current smokers (healthy smokers and COPD current smokers) and non/ex-smokers (nonsmokers and COPD ex-smokers), plasma CXCL8, CCL22, CCL4, and MVD were greater in current smokers. No differences in other cytokines were seen. Plasma CXCL8 moderately correlated with MVD (r = 0.552, p = 0.003). DISCUSSION: In this small cohort, circulating levels of the chemokines CXCL8, CCL4, and CCL22, as well as MVD, attain the highest levels in healthy smokers compared to nonsmokers and COPD subjects. These findings seem to be driven by current smoking and are independent of airflow obstruction. CONCLUSIONS: These data suggest that smoking upregulates a systemic pattern of neutrophil and macrophage chemoattractant expression, and this correlates significantly with the development of goblet cell hyperplasia.
Asunto(s)
Quimiocinas/inmunología , Células Caliciformes/patología , Pulmón/patología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Fumar/inmunología , Adulto , Anciano , Estudios de Casos y Controles , Quimiocina CCL2/inmunología , Quimiocina CCL22/inmunología , Quimiocina CCL3/inmunología , Quimiocina CCL4/inmunología , Quimiocina CCL7/inmunología , Citocinas/inmunología , Factor de Crecimiento Epidérmico/inmunología , Femenino , Humanos , Hiperplasia/inmunología , Hiperplasia/patología , Interleucina-1/inmunología , Interleucina-17/inmunología , Interleucina-4/inmunología , Interleucina-6/inmunología , Interleucina-8/inmunología , Interleucina-9/inmunología , Masculino , Persona de Mediana Edad , Mucinas , Enfermedad Pulmonar Obstructiva Crónica/patología , Fumar/patología , Factor A de Crecimiento Endotelial Vascular/inmunologíaRESUMEN
We evaluated the utility of chemokine MCP-3 and MDC/CCL22 as molecular adjuvants of DNA vaccines for botulinum neurotoxin serotype A (BoNT/A) in a Balb/c mouse model. Notably, the immunogenicity of the DNA vaccine against BoNT/A was not enhanced using a fusion of the AHc-C antigen with the MCP-3 or MDC/CCL22. Nevertheless, the potency of the DNA vaccine was significantly modulated and enhanced by co-administration of the AHc-C antigen with MCP-3 or MDC/CCL22. This strategy elicited high levels of humoral immune responses and protection against BoNT/A. The enhanced potency was further boosted by co-administration of the AHc-C antigen with both MCP-3 and MDC/CCL22 in Balb/c mice, but not by co-administration of AHc-C antigen with the MCP-3-MDC/CCL22 fusion. Co-immunization with both the MCP-3 and MDC/CCL22 constructs induced the highest levels of humoral immunity and protective potency against BoNT/A. Our results indicated that MCP-3 and MDC/CCL22 are effective molecular adjuvants of the immune responses induced by the AHc-C-expressing DNA vaccine when delivered by co-administration of the individual chemokines, but not when delivered in the form of a chemokine/antigen fusion. Thus, we describe an alternative strategy to the design and optimization of DNA vaccine constructs based on co-administration of the antigen with the chemokine rather than in the form of a chemokine/antigen fusion.
Asunto(s)
Antígenos/inmunología , Toxinas Botulínicas Tipo A/inmunología , Quimiocina CCL22/inmunología , Quimiocina CCL7/inmunología , Vacunas de ADN , Animales , Femenino , Inmunoglobulina G/sangre , Ratones Endogámicos BALB C , Potencia de la VacunaRESUMEN
First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1- and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFα, CXCL1, CCL7, IFN-α2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum level of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstrate an association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.
Asunto(s)
Apolipoproteína A-I/inmunología , Quimiocina CCL22/inmunología , Lóbulo Frontal/inmunología , Inmunidad Innata , Trastornos Psicóticos/inmunología , Sustancia Blanca/inmunología , Adolescente , Adulto , Anisotropía , Antipsicóticos/uso terapéutico , Apolipoproteína A-I/sangre , Estudios de Casos y Controles , Quimiocina CCL22/sangre , Quimiocina CCL7/sangre , Quimiocina CCL7/inmunología , Quimiocina CXCL1/sangre , Quimiocina CXCL1/inmunología , Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Expresión Génica/inmunología , Sustancia Gris/inmunología , Sustancia Gris/metabolismo , Sustancia Gris/patología , Humanos , Procesamiento de Imagen Asistido por Computador , Interferón-alfa/sangre , Interferón-alfa/inmunología , Masculino , Trastornos Psicóticos/sangre , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/patología , Factor de Crecimiento Transformador alfa/sangre , Factor de Crecimiento Transformador alfa/inmunología , Sustancia Blanca/metabolismo , Sustancia Blanca/patologíaRESUMEN
Rhinovirus (RV) infections are common and have the potential to exacerbate asthma. We have determined the lung transcriptome in RV strain 1B-infected naive BALB/c mice (nonallergic) and identified CCL7 and IFN regulatory factor (IRF)-7 among the most upregulated mRNA transcripts in the lung. To investigate their roles we employed anti-CCL7 Abs and an IRF-7-targeting small interfering RNA in vivo. Neutralizing CCL7 or inhibiting IRF-7 limited neutrophil and macrophage influx and IFN responses in nonallergic mice. Neutralizing CCL7 also reduced activation of NF-κB p65 and p50 subunits, as well as airway hyperreactivity (AHR) in nonallergic mice. However, neither NF-κB subunit activation nor AHR was abolished with infection of allergic mice after neutralizing CCL7, despite a reduction in the number of neutrophils, macrophages, and eosinophils. IRF-7 small interfering RNA primarily suppressed IFN-α and IFN-ß levels during infection of allergic mice. Our data highlight a pivotal role of CCL7 and IRF-7 in RV-induced inflammation and IFN responses and link NF-κB signaling to the development of AHR.
Asunto(s)
Quimiocina CCL7/inmunología , Resfriado Común/inmunología , Factor 7 Regulador del Interferón/inmunología , Interferones/inmunología , Pulmón/inmunología , Animales , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/virología , Modelos Animales de Enfermedad , Citometría de Flujo , Inflamación/inmunología , Inflamación/virología , Masculino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Rhinovirus/inmunología , TranscriptomaRESUMEN
Macrophages are important in vascular inflammation and environmental factors influence macrophage plasticity. Macrophage transitions into pro-inflammatory (M1) or anti-inflammatory (M2) states have been defined predominately by measuring cytokines in culture media (CM). However, temporal relationships between cellular and secreted cytokines have not been established. We measured phenotypic markers and cytokines in cellular and CM of murine bone marrow-derived macrophages at multiple time points following stimulation with IFN-γ + LPS (M1), IL-4 (M2a) or IL-10 (M2c). Cytokines/proteins in M1-polarized macrophages exhibited two distinct temporal patterns; an early (0.5-3 h), transient increase in cellular cytokines (GM-CSF, KC-GRO, MIP-2, IP-10 and MIP-1ß) and a delayed (3-6 h) response that was more sustained [IL-3, regulated on activation normal T cell expressed and secreted (RANTES), and tissue inhibitor of metalloproteinases 1 (TIMP-1)]. M2a-related cytokine/cell markers (IGF-1, Fizz1 and Ym1) were progressively (3-24 h) increased post-stimulation. In addition, novel patterns were observed. First, and unexpectedly, cellular pro-inflammatory chemokines, MCP-1 and MCP-3 but not MCP-5, were comparably increased in M1 and M2a macrophages. Second, Vegfr1 mRNA was decreased in M1 and increased in M2a macrophages. Finally, VEGF-A was increased in the CM of M1 cultures and strikingly reduced in M2a coinciding with increased Vegfr1 expression, suggesting decreased VEGF-A in M2a CM was secondary to increased soluble VEGFR1. In conclusion, macrophage cytokine production and marker expression were temporally regulated and relative levels compared across polarizing conditions were highly dependent upon the timing and location (cellular versus CM) of the sample collection. For most cytokines, cellular production preceded increases in the CM suggesting that cellular regulatory pathways should be studied within 6 h of stimulation. The divergent polarization-dependent expression of Vegfr1 may be essential to controlling VEGF potentially regulating angiogenesis and inflammatory cell infiltration in the vascular niche. The current study expands the repertoire of cytokines produced by polarized macrophages and provides insights into the dynamic regulation of macrophage polarization and resulting cytokines, proteins and gene expression that influence vascular inflammation.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Macrófagos/efectos de los fármacos , Fenotipo , Factor A de Crecimiento Endotelial Vascular/inmunología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/inmunología , Animales , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL4/genética , Quimiocina CCL4/inmunología , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Quimiocina CXCL2/genética , Quimiocina CXCL2/inmunología , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Interferón gamma/farmacología , Interleucina-10/farmacología , Interleucina-4/farmacología , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/inmunología , Ratones , Cultivo Primario de Células , Transducción de Señal , Factores de Tiempo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/inmunología , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Advances in microsurgical techniques and immunosuppressive medication have rendered transplantation of vascularized composite allografts possible, when autologous tissue is neither available nor sufficient for reconstruction. However, skin rejection and side effects of long-term immunosuppression still remain a major hurdle for wide adoption of this excellent reconstructive technique. Histopathologic changes during acute skin rejection in vascular composite allotransplantation often mimic inflammatory skin disorders and are hard to distinguish. Hence, the identification of diagnostic and therapeutic markers specific for skin rejection is of particular clinical need. Here we present novel markers allowing for early differentiation between rejection in hind limb allotransplantation and contact hypersensitivity. Assessment of Ccl7, Il18, and Il1b expression is most indicative of distinguishing skin rejection from skin inflammatory disorders. Gene expression levels varied significantly across skin types and regions, indicating localization specific mechanism of leukocyte migration and infiltration. Expression of Il12b, Il17a, and Il1b gene expression levels differed significantly between rejection and inflammation, independent of the skin type. In synopsis of the RNA expression profile and previously assessed protein expression, the Il1 family appears as a promising option for accurate skin rejection diagnosis and, as a following step, for development of novel rejection treatments.
Asunto(s)
Diferenciación Celular/inmunología , Expresión Génica/inmunología , Rechazo de Injerto/inmunología , Inflamación/inmunología , Piel/inmunología , Linfocitos T/inmunología , Animales , Diferenciación Celular/fisiología , Movimiento Celular/inmunología , Quimiocina CCL7/inmunología , Rechazo de Injerto/patología , Miembro Posterior/inmunología , Miembro Posterior/patología , Terapia de Inmunosupresión/métodos , Inflamación/patología , Interleucina-1/inmunología , Interleucina-18/inmunología , Leucocitos/inmunología , Masculino , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Piel/patología , Linfocitos T/patología , Trasplante Homólogo/métodosRESUMEN
FTY720, an agonist for four of the five known sphingosine-1-phosphate (S1P) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple S1P receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective S1P receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an S1P1-selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an S1P1-selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Indanos/farmacología , Macrófagos/efectos de los fármacos , Oxadiazoles/farmacología , Receptores de Lisoesfingolípidos/agonistas , Animales , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Modelos Animales de Enfermedad , Clorhidrato de Fingolimod/farmacología , Regulación de la Expresión Génica , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inmunosupresores/farmacología , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/patología , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Irradiación Corporal TotalRESUMEN
In a search for factors up-regulated by mechanical strain in osteocytes, we discovered that chemokine (C-C motif) ligand 7 (CCL7), a chemotactic myokine, was highly expressed in MLO-Y4 osteocyte-like cells. Although MLO-Y4 cells secrete potent chemotactic factors for osteoclast precursors, CCL7 was not responsible for this activity. CCL7 was increased in osteocytes in response to tooth movement in vivo. Since mechanical loading plays a crucial role in maintaining osteocyte viability, CCL7 was tested for protective activity and found to be protective against cell death induced by dexamethasone and etoposide. CCL7 specific antibody partially, but in combination with indomethacin, completely abrogated the protective effects of fluid flow shear stress against dexamethasone-induced cell death. CCL7 activated the ß-catenin pathway through phosphorylation of glycogen synthase kinase 3 (GSK-3), suggesting that this pathway is responsible for the observed protective effects. A related cytokine, CCL2, also produced by MLO-Y4 cells but not regulated by mechanical loading, proved to be more potent and protected against cell death induced by not only dexamethasone, but also by Tumor Necrosis Factor α (TNFα). Whereas osteocytes may produce CCL2 in constitutively low levels, a major function of mechanically induced CCL7 may be to selectively protect osteocytes in an autocrine manner against glucocorticoid-induced cell death.