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1.
Front Immunol ; 12: 650176, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512619

RESUMO

Diabetes-related cognitive dysfunction (DRCD) is a serious complication induced by diabetes. However, there are currently no specific remedies for DRCD. Here, we show that streptozotocin-induced DRCD can be prevented without causing side effects through oral administration of lipopolysaccharide (LPS) derived from Pantoea agglomerans. Oral administration of LPS (OAL) prevented the cerebral cortex atrophy and tau phosphorylation induced by DRCD. Moreover, we observed that neuroprotective transformation of microglia (brain tissue-resident macrophages) is important for preventing DRCD through OAL. These findings are contrary to the general recognition of LPS as an inflammatory agent when injected systemically. Furthermore, our results strongly suggest that OAL promotes membrane-bound colony stimulating factor 1 (CSF1) expression on peripheral leukocytes, which activates the CSF1 receptor on microglia, leading to their transformation to the neuroprotective phenotype. Taken together, the present study indicates that controlling innate immune modulation through the simple and safe strategy of OAL can be an innovative prophylaxis for intractable neurological diseases such as DRCD. In a sense, for modern people living in an LPS-depleted environment, OAL is like a time machine that returns microglia to the good old LPS-abundant era.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Complicações do Diabetes/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Pantoea/química , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/prevenção & controle , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais
2.
Mol Med Rep ; 24(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328201

RESUMO

Diabetes­associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2­deoxy­2­(3­methy1­3­nitrosoureido) D­glucopyranose; STZ] is one of the most well­established diabetes inducers and has been used in vivo and in vitro DAND models. The aim of the present study was to demonstrate that C8­B4 microglia transformed by the stimulus of repetitive low­dose lipopolysaccharide (LPSx3­microglia) prevent STZ­induced Neuro­2a neuronal cell death in vitro. The ELISA results showed that neurotrophin­4/5 (NT­4/5) secretion was promoted in LPSx3­microglia and the cell viability assay with trypan blue staining revealed that the culture supernatant of LPSx3­microglia prevented STZ­induced neuronal cell death. In addition, reverse transcription­quantitative PCR showed that neurons treated with the culture supernatant of LPSx3­microglia promoted the gene expression of B­cell lymphoma­extra large and glucose­dependent insulinotropic polypeptide receptor. Furthermore, the inhibition of tyrosine kinase receptor B, a receptor of NT­4/5, suppressed the neuroprotective effect of LPSx3­microglia. Taken together, the present study demonstrated that LPSx3­microglia prevent STZ­induced neuronal death and that NT­4/5 may be involved in the neuroprotective mechanism of LPSx3­microglia.


Assuntos
Morte Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Neurônios/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores dos Hormônios Gastrointestinais/genética , Estreptozocina/farmacologia , Proteína bcl-X/genética
3.
Anticancer Res ; 41(8): 4053-4059, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281874

RESUMO

BACKGROUND/AIM: Diabetes is a risk factor for dementia. However, no radical preventive method for diabetes-associated dementia has yet been developed. Our previous study revealed that oral administration of lipopolysaccharide (LPS) prevents high-fat diet-induced cognitive impairment. Therefore, we investigated here whether oral administration of LPS (OAL) could also prevent diabetes-associated dementia. MATERIALS AND METHODS: Diabetic mice were produced by intraperitoneal administration of streptozotocin (STZ), and then mice were orally administered LPS. Cognitive ability was evaluated using the Morris water maze, and gene expression was analyzed in isolated microglia. RESULTS: OAL prevented STZ-induced diabetic cognitive impairment, but did not affect blood glucose levels. Moreover, OAL promoted the expression of neuroprotective genes in microglia, such as heat shock protein family 40 (HSP40) and chemokine CCL7. CONCLUSION: OAL prevents diabetes-associated dementia, potentially via promotion of HSP40 and CCL7 expression in microglia.


Assuntos
Disfunção Cognitiva/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Lipopolissacarídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Quimiocina CCL7/genética , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Proteínas de Choque Térmico HSP40/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia
4.
Anticancer Res ; 40(8): 4457-4464, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727775

RESUMO

BACKGROUND/AIM: Our previous studies suggested that oral administration of lipopolysaccharide (LPS) regulates the progression of various diseases via transformation of tissue-resident macrophages (MΦ). Recently, we characterized microglia transformed by repetitive low-dose LPS treatment (REPELL-microglia) in vitro, and this response was similar to that observed in response to oral administration of LPS in vivo. Here, we examined the characteristics of peritoneal tissue-resident MΦ (pMΦ) transformed by repetitive low-dose LPS treatment (REPELL-pMΦ). MATERIALS AND METHODS: Primary pMΦ were treated with low-dose LPS (1 ng/ml) three times; subsequently, phagocytic activity and gene expression were evaluated. RESULTS: REPELL-pMΦ exhibited high phagocytic activity and elevated expression of Arg1, Gipr, Gdnf, and Fpr2. The gene expression profiles observed in REPELL-pMΦ were distinct from those of REPELL-microglia. CONCLUSION: REPELL-pMΦ have the potential to promote clearance of xenobiotics and to suppress inflammation. The present study also demonstrates the diversity of tissue-resident MΦ transformation that reflect their tissue origin.


Assuntos
Arginase/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Lipopolissacarídeos/efeitos adversos , Macrófagos Peritoneais/fisiologia , Receptores de Formil Peptídeo/genética , Receptores dos Hormônios Gastrointestinais/genética , Administração Oral , Animais , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/administração & dosagem , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Especificidade de Órgãos , Fagocitose/efeitos dos fármacos , Fenótipo , Cultura Primária de Células , Regulação para Cima
5.
Anticancer Res ; 40(8): 4711-4717, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727797

RESUMO

BACKGROUND: Continuous oral administration of lipopolysaccharide (LPS) enhances the phagocytic ability of macrophages, which is useful for preventing various diseases. Here, we attempted to create an in vitro model of continuous administration of LPS. MATERIALS AND METHODS: RAW264.7 cells were stimulated with LPS three times every 24 h (repeated stimulation), and phagocytic ability and inflammatory cytokine [interleukin-6 (IL6) and tumor necrosis factor-α (TNFα)] production were measured. RESULTS: The phagocytic ability was increased by a single stimulation with LPS and was maintained by repeated stimulation. IL6 production increased with a single stimulation with LPS; however, IL6 production by repeated stimulation with LPS was comparable to that of non-stimulation with LPS. On the other hand, the amount of TNFα was significantly increased by single and repeated stimulation with LPS. CONCLUSION: Repeated stimulation with LPS in RAW264.7 cells triggered a phenotype that was similar to that of macrophages after continuous oral administration of LPS. This suggests that this study model may reproduce the enhancement of macrophage phagocytosis, an effect afforded by continuous oral administration of LPS.


Assuntos
Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
6.
Sci Rep ; 10(1): 8945, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488176

RESUMO

Although lipopolysaccharide (LPS) is regarded as an inducer of inflammation, previous studies have suggested that repetitive low-dose LPS has neuroprotective effects via immunomodulation of microglia, resident macrophages of brain. However, microglia transformed by the stimulus of repetitive low-dose LPS (REPELL-microglia) are not well characterized, whereas microglia transformed by repetitive high-dose LPS are well studied as an endotoxin tolerance model in which the induction of pro-inflammatory molecules is suppressed. In this study, to characterize REPELL-microglia, the gene expression and phagocytic activity of REPELL-microglia were analyzed with the murine C8-B4 microglia cell line. The REPELL-microglia were characterized by a high expression of pro-inflammatory molecules (Nos2, Ccl1, IL-12B, and CD86), anti-inflammatory molecules (IL-10, Arg1, Il13ra2, and Mrc1), and neuroprotective molecules (Ntf5, Ccl7, and Gipr). In addition, the phagocytic activity of REPELL-microglia was promoted as high as that of microglia transformed by single low-dose LPS. These results suggest the potential of REPELL-microglia for inflammatory regulation, neuroprotection, and phagocytic clearance. Moreover, this study revealed that gene expression of REPELL-microglia was distinct from that of microglia transformed by repetitive high-dose LPS treatment, suggesting the diversity of microglia transformation by different doses of LPS.


Assuntos
Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fenótipo , Transdução de Sinais/efeitos dos fármacos
7.
PLoS Negl Trop Dis ; 14(1): e0008020, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961866

RESUMO

Myeloid-related protein 14 (MRP14) belongs to the S100 calcium-binding protein family and is expressed in neutrophils and inflammatory macrophages. Increase in the number of MRP14+ cells or serum level of MRP14 is associated with various diseases such as autoimmune diseases and infectious diseases, suggesting the involvement of the molecule in pathogenesis of those diseases. In this study, to examine the pathological involvement of MRP14 during cutaneous and visceral leishmaniasis, wild-type (WT) and MRP14 knockout (MRP14KO) mice were infected with Leishmania major and L. donovani. Increase in the number of MRP14+ cells at the infection sites in wild-type mice was commonly found in the skin during L. major infection as well as the spleen and liver during L. donovani infection. In contrast, the influence of MRP14 to the pathology seemed different between the two infections. MRP14 depletion exacerbated the lesion development and ulcer formation in L. major infection. On the other hand, the depletion improved anemia and splenomegaly but not hepatomegaly at 24 weeks of L. donovani infection. These results suggest that, distinct from its protective role in CL, MRP14 is involved in exacerbation of some symptoms during VL.


Assuntos
Anemia/metabolismo , Anemia/patologia , Calgranulina B/metabolismo , Leishmaniose Visceral/metabolismo , Leishmaniose Visceral/patologia , Esplenomegalia/metabolismo , Esplenomegalia/patologia , Anemia/genética , Anemia/parasitologia , Animais , Calgranulina B/genética , Feminino , Humanos , Leishmania donovani/fisiologia , Leishmania major/fisiologia , Leishmaniose Visceral/genética , Leishmaniose Visceral/parasitologia , Fígado/metabolismo , Fígado/parasitologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Baço/metabolismo , Baço/parasitologia , Baço/patologia , Esplenomegalia/genética , Esplenomegalia/parasitologia
8.
PLoS One ; 13(6): e0199111, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29902248

RESUMO

Hepatic dysfunction is one of the clinical features in severe malaria. However, the mechanism of hepatic injury during malaria is still unknown. Myeloid-related protein (MRP) 14 is abundantly expressed by myeloid cells and involved in various inflammatory diseases. We previously reported that serum MRP14 is elevated in mice infected with Plasmodium berghei ANKA. In order to verify whether extracellular MRP14 is involved in the pathology of hepatic injury during rodent malaria, we intravenously administrated recombinant MRP14 (rMRP14) to mice infected with P. berghei ANKA. The administration of rMRP14 did not affect parasite number or hematocrit. On the other hand, the hepatic injury was exacerbated in rMRP14-treated mice, and their serum concentration of hepatic enzymes increased significantly more than PBS-treated controls. Immunohistochemical analysis of the liver showed that more MRP14+ macrophages accumulated in rMRP14-treated mice than PBS-treated controls after infection. The administration of rMRP14 also promotes the up-regulation of pro-inflammatory molecules in the liver, such as iNOS, IL-1ß, IL-12, and TNF-α. Even in the absence of Plasmodium infection, administration of rMRP14 could induce the accumulation of MRP14+ macrophages and up-regulation of the pro-inflammatory molecules in the liver of naïve mice. The results indicate that MRP14 promotes the accumulation of MRP14+ cells and the up-regulation of pro-inflammatory molecules and NO, which amplify inflammatory cascade leading to hepatic injury. In conclusion, MRP14 is a one of key molecules for liver inflammation during rodent malaria.


Assuntos
Calgranulina B/metabolismo , Fígado/lesões , Fígado/metabolismo , Malária/metabolismo , Animais , Calgranulina B/sangue , Espaço Extracelular/metabolismo , Fígado/patologia , Ativação de Macrófagos , Camundongos , Plasmodium berghei/fisiologia , Células RAW 264.7
9.
Immunol Lett ; 194: 13-20, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29253495

RESUMO

Myeloid-related protein (MRP) 14 and MRP8 are abundantly expressed by myeloid cells and are involved in various inflammatory disorders. Although accumulating evidence revealed the roles of MRP14 and MRP8 in inflammatory responses by using MRP14-knockout (KO) mice, the KO mice were only available in the C57BL/6 background. We established BALB/c-background MRP14-KO mice to examine if its biological functions are conserved in mice with a different genetic background. MRP14-KO BALB/c mice showed different phenotypes from the reported MRP14-KO C57BL/6 mice in terms of bone marrow cell response to LPS and peripheral leukocyte population. When an acute lethal dose of LPS was injected, the survival rate was not different between MRP14-KO and WT mice, which was also different from results previously reported on C57BL/6 mice. These results suggest that immunological functions of MRP14, and possibly also the associated molecule MRP8, are different between BALB/c and C57BL/6 mice, at least in the response to LPS.


Assuntos
Calgranulina B/imunologia , Lipopolissacarídeos/toxicidade , Choque Séptico/imunologia , Animais , Calgranulina A/genética , Calgranulina B/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Choque Séptico/induzido quimicamente , Choque Séptico/genética , Choque Séptico/patologia , Especificidade da Espécie
10.
Exp Parasitol ; 138: 1-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24440297

RESUMO

Splenomegaly is one of the typical symptoms of malaria. However, the pathogenesis of splenic enlargement still remains unclear. Spleen is a major organ for clearance of malaria parasites, but excessive response to the parasites can lead to splenomegaly. Myeloid-related protein (MRP) 8 and MRP14 are expressed by myeloid cells and are regarded as marker proteins of an immature and inflammatory subtype of macrophage. Previous studies have demonstrated that accumulation of MRP8(+) and MRP14(+) macrophages is associated with the pathological changes associated with various inflammatory diseases. In order to elucidate whether MRP8(+) and MRP14(+) cells are also involved in splenomegaly during malaria, we investigated expression of MRP8 and MRP14 in the spleens of mice infected with Plasmodium berghei. The MRP8 and MRP14 levels in the serum were analyzed by western blot, which confirmed that these proteins were elevated during infection compared with uninfected controls. Enlargement of the spleen was prominent at 7days of infection, and histological analysis of the spleens demonstrated deposition of malaria pigments and accumulation of mononuclear cells. Immunohistochemical staining of the tissue revealed the accumulation of cells expressing MRP8 and MRP14. In addition, the locations of those cells overlapped with CD11b(+) cells in the red pulp. These results suggest that splenomegaly in malaria is partly due to the accumulation of MRP8(+) and MRP14(+) macrophages.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Macrófagos/imunologia , Malária/imunologia , Plasmodium berghei/imunologia , Baço/imunologia , Animais , Western Blotting , Encéfalo/patologia , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Calgranulina A/sangue , Calgranulina B/sangue , Eritrócitos/parasitologia , Imuno-Histoquímica , Rim/química , Rim/patologia , Macrófagos/metabolismo , Malária/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/imunologia , Parasitemia/patologia , Organismos Livres de Patógenos Específicos , Baço/citologia , Baço/patologia , Esplenomegalia/etiologia
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