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1.
Immunology ; 164(2): 305-317, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34002852

RESUMO

Gout is an inflammatory disease triggered by deposition of monosodium urate (MSU) crystals in the joints, resulting in high neutrophil influx and pain. Here, we studied the role of the inhibitory receptor CD300a in the resolution process in a murine model of gout. We found increased CD300a expression on neutrophils emigrated to the joint. When compared to WT mice, CD300a-/- mice had persistent neutrophil influx till 24 hr after MSU injection. This was associated with increased concentration of IL-1ß and greater tissue damage in the joints of CD300a-/- mice. There was an increase in the percentage of apoptotic neutrophils in the synovial lavage of WT mice, as compared to CD300a-/- mice. This difference was reflected in the decline of efferocytic events in the synovial cavity of CD300a-/- mice 24 hr after MSU injection. A CD300a agonistic antibody was shown, for the first time, to increase apoptosis of human neutrophils, and this was associated with cleavage of caspase-8. In conclusion, our results reveal an important role of CD300a in the control of leucocyte infiltration, IL-1ß production and caspase-8 cleavage in neutrophils, contributing to the resolution of inflammation triggered by MSU injection.


Assuntos
Antígenos CD/imunologia , Apoptose/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , Receptores Imunológicos/imunologia , Ácido Úrico/imunologia , Animais , Células Cultivadas , Gota/imunologia , Humanos , Interleucina-1beta/imunologia , Articulações/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
2.
Pharmacol Res ; 163: 105292, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33171305

RESUMO

Resolution failure of exacerbated inflammation triggered by Influenza A virus (IAV) prevents return of pulmonary homeostasis and survival, especially when associated with secondary pneumococcal infection. Therapeutic strategies based on pro-resolving molecules have great potential against acute inflammatory diseases. Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator that acts on its Mas receptor (MasR) to promote resolution of inflammation. We investigated the effects of Ang-(1-7) and the role of MasR in the context of primary IAV infection and secondary pneumococcal infection and evaluated pulmonary inflammation, virus titers and bacteria counts, and pulmonary damage. Therapeutic treatment with Ang-(1-7) decreased neutrophil recruitment, lung injury, viral load and morbidity after a primary IAV infection. Ang-(1-7) induced apoptosis of neutrophils and efferocytosis of these cells by alveolar macrophages, but had no direct effect on IAV replication in vitro. MasR-deficient (MasR-/-) mice were highly susceptible to IAV infection, displaying uncontrolled inflammation, increased viral load and greater lethality rate, as compared to WT animals. Ang-(1-7) was not protective in MasR-/- mice. Interestingly, Ang-(1-7) given during a sublethal dose of IAV infection greatly reduced morbidity associated with a subsequent S. pneumoniae infection, as seen by decrease in the magnitude of neutrophil influx, number of bacteria in the blood leading to a lower lethality. Altogether, these results show that Ang-(1-7) is highly protective against severe primary IAV infection and protects against secondary bacterial infection of the lung. These effects are MasR-dependent. Mediators of resolution of inflammation, such as Ang-(1-7), should be considered for the treatment of pulmonary viral infections.


Assuntos
Angiotensina I/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Infecções Pneumocócicas/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Proteínas Proto-Oncogênicas/imunologia , Receptores Acoplados a Proteínas G/imunologia , Células A549 , Angiotensina I/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Cães , Humanos , Vírus da Influenza A , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fragmentos de Peptídeos/farmacologia , Peroxidase/imunologia , Fagocitose/efeitos dos fármacos , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas G/genética , Streptococcus pneumoniae
3.
J Leukoc Biol ; 106(4): 957-966, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31107994

RESUMO

CD300a is an inhibitory immunoreceptor expressed in lymphoid and myeloid cells. This study evaluates whether CD300a plays a role in the control of joint inflammation in a model of Ag-induced arthritis (AIA) in mice. CD300a was found to be expressed mostly on neutrophils and its expression was enhanced on neutrophils that migrated to the inflamed synovial cavity. Joint inflammation, as characterized by neutrophil accumulation, was significantly greater in CD300a KO (CD300a-/- ) mice subjected to AIA, as compared to WT mice. This was associated with joint dysfunction, as measured by lower mechanical nociception threshold. There was greater production of the chemokine CXCL1 and the cytokine IL-6 in joints of CD300a-/- mice. In vitro, Mϕs from CD300a-/- mice released higher concentrations of CXCL1 and IL-6 in response to LPS. Splenocytes from immunized CD300a-/- mice produced increased levels of IFN-γ and IL-17 and lower levels of IL-10 when challenged with Ag than cells from WT mice. Neutrophils lacking the CD300a gene had greater chemotactic activity in response to fMLP, CXCL1, and LTB4 than WT neutrophils. In conclusion, these results reveal that the absence of CD300a promotes exacerbation of inflammation in a model of Ag-induced arthritis, suggesting that CD300a is an important receptor for negatively controlling the inflammatory response in this model. Mechanistically, CD300a seems to regulate the activity of various immune cells types involved in the process, including neutrophils, Mϕs, and lymphocytes.


Assuntos
Antígenos/efeitos adversos , Artrite Experimental/metabolismo , Artrite Experimental/fisiopatologia , Inflamação/patologia , Receptores Imunológicos/metabolismo , Animais , Anticorpos/metabolismo , Artrite Experimental/patologia , Quimiotaxia , Citocinas/biossíntese , Progressão da Doença , Inflamação/complicações , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos , Neutrófilos/patologia , Nociceptividade , Dor/complicações , Dor/patologia , Baço/patologia , Membrana Sinovial/patologia , Fatores de Tempo
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