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1.
Front Immunol ; 13: 818266, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35197983

RESUMO

Visceral leishmaniasis, caused by L. donovani infection is fatal if left untreated. The intrinsic complexity of visceral leishmaniasis complicated further by the increasing emergence of drug resistant L. donovani strains warrants fresh investigations into host defense schemes that counter infections. Accordingly, in a mouse model of experimental visceral leishmaniasis we explored the utility of host Wnt5A in restraining L. donovani infection, using both antimony sensitive and antimony resistant L. donovani strains. We found that Wnt5A heterozygous (Wnt5A +/-) mice are more susceptible to L. donovani infection than their wild type (Wnt5A +/+) counterparts as depicted by the respective Leishman Donovan Units (LDU) enumerated from the liver and spleen harvested from infected mice. Higher LDU in Wnt5A +/- mice correlated with increased plasma gammaglobulin level, incidence of liver granuloma, and disorganization of splenic white pulp. Progression of infection in mice by both antimony sensitive and antimony resistant strains of L. donovani could be prevented by activation of Wnt5A signaling through intravenous administration of rWnt5A prior to L. donovani infection. Wnt5A mediated blockade of L. donovani infection correlated with the preservation of splenic macrophages and activated T cells, and a proinflammatory cytokine bias. Taken together our results indicate that while depletion of Wnt5A promotes susceptibility to visceral leishmaniasis, revamping Wnt5A signaling in the host is able to curb L. donovani infection irrespective of antimony sensitivity or resistance and mitigate the progression of disease.


Assuntos
Leishmaniose Visceral/prevenção & controle , Animais , Antimônio/uso terapêutico , Citocinas/uso terapêutico , Leishmania donovani/fisiologia , Ativação Linfocitária , Macrófagos/imunologia , Camundongos , Transdução de Sinais , Baço/imunologia , Proteína Wnt-5a
2.
FASEB J ; 34(9): 12163-12176, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32686858

RESUMO

Cellular communication network factor 6 (CCN6) mutations are linked with Progressive Pseudo Rheumatoid Dysplasia (PPRD) a debilitating musculoskeletal disorder. The function of CCN6 and the mechanism of PPRD pathogenesis remain unclear. Accordingly, we focused on the functional characterization of CCN6 and CCN6 mutants. Using size exclusion chromatography and native polyacrylamide gel electrophoresis we demonstrated that CCN6 is present as a component of the mitochondrial respiratory complex in human chondrocyte lines. By means of siRNA-mediated transfection and electron microscopy we showed that moderate reduction in CCN6 expression decreases the RER- mitochondria inter-membrane distance. Parallel native PAGE, immunoblotting and Complex I activity assays furthermore revealed increase in both mitochondrial distribution of CCN6 and mitochondrial respiratory complex assembly/activity in CCN6 depleted cells. CCN6 mutants resembling those linked with PPRD, which were generated by CRISPR-Cas9 technology displayed low level of expression of mutant CCN6 protein and inhibited respiratory complex assembly/activity. Electron microscopy and MTT assay of the mutants revealed abnormal mitochondria and poor cell viability. Taken together, our results indicate that CCN6 regulates mitochondrial respiratory complex assembly/activity as part of the mitochondrial respiratory complex by controlling the proximity of RER with the mitochondria, and CCN6 mutations disrupt mitochondrial respiratory complex assembly/activity resulting in mitochondrial defects and poor cell viability.


Assuntos
Proteínas de Sinalização Intercelular CCN/metabolismo , Condrócitos/metabolismo , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas de Sinalização Intercelular CCN/genética , Linhagem Celular , Transporte de Elétrons , Humanos , Mitocôndrias/genética , Mutação
3.
Front Immunol ; 9: 679, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29686674

RESUMO

Bacterial pathogens are associated with severe infections (e.g., sepsis) and exacerbation of debilitating conditions such as chronic obstructive pulmonary disease (COPD). The interactions of bacterial pathogens with macrophages, a key component of innate immunity and host defense, are not clearly understood and continue to be intensively studied. Having previously demonstrated a role of Wnt5A signaling in phagocytosis, we proceeded to decipher the connection of Wnt5A signaling with infection by pathogenic bacteria, namely Pseudomonas aeruginosa (PA) and Streptococcus pneumoniae (SP), which are related with the progression of COPD and sepsis. We found that during the initial hours of infection with PA and SP, there is decrease in the steady state levels of the Wnt5A protein in macrophages. Suppression of Wnt5A signaling, moreover, impairs macrophage clearance of the bacterial infection both in vitro and in vivo. Activation of Wnt5A signaling, on the other hand, enhances clearance of the infection. Macrophage-mediated containment of bacterial infection in our study is dependant on Wnt5A-induced Rac1/Disheveled activation and cytochalasin D inhibitable actin assembly, which is associated with ULK1 kinase activity and LC3BII accumulation. Our experimental findings are consistent with Wnt5A signaling-dependent induction of autophagic killing (xenophagy) of PA and SP, as further substantiated by transmission electron microscopy. Overall, our study unveils the prevalence of a Wnt5A-Rac1-Disheveled-mediated actin-associated autophagy circuit as an important component of innate immunity in host macrophages that may turn out crucial for restricting infection by leading bacterial pathogens.


Assuntos
Proteínas Desgrenhadas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Neuropeptídeos/imunologia , Infecções Pneumocócicas/imunologia , Infecções por Pseudomonas/imunologia , Proteína Wnt-5a/imunologia , Proteínas rac1 de Ligação ao GTP/imunologia , Animais , Linhagem Celular , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Peritonite/imunologia , Pseudomonas aeruginosa , Infecções Respiratórias/imunologia , Streptococcus pneumoniae
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