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1.
Cell Metab ; 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39260371

RESUMEN

Rheumatoid arthritis (RA) is a chronic autoimmune condition characterized by inflammatory activity with distinct rhythmic fluctuations. However, the precise mechanisms governing these inflammatory rhythms remain elusive. Here, we explore the interaction between dietary patterns, gut microbiota diurnal oscillations, and the rhythmicity of RA in both collagen-induced arthritis (CIA) mice and patients with RA and highlight the significance of dietary timing in modulating RA inflammatory rhythms linked to gut microbiota. Specifically, we discovered that Parabacteroides distasonis (P. distasonis) uses ß-glucosidase (ß-GC) to release glycitein (GLY) from the diet in response to daily nutritional cues, influencing RA inflammatory rhythms dependent on the sirtuin 5-nuclear factor-κB (SIRT5-NF-κB) axis. Notably, we validated the daily fluctuations of P. distasonis-ß-GC-GLY in patients with RA through continuous sampling across day-night cycles. These findings underscore the crucial role of dietary timing in RA rhythmicity and propose potential clinical implications for novel therapeutic strategies to alleviate arthritis.

2.
Int Immunopharmacol ; 133: 112058, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38613883

RESUMEN

Fetal growth restriction (FGR) is a major cause of premature and low-weight births, which increases the risk of necrotizing enterocolitis (NEC); however, the association remains unclear. We report a close correlation between placental polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and NEC. Newborns with previous FGR exhibited intestinal inflammation and more severe NEC symptoms than healthy newborns. Placental PMN-MDSCs are vital regulators of fetal development and neonatal gut inflammation. Placental single-cell transcriptomics revealed that PMN-MDSCs populations and olfactomedin-4 gene (Olfm4) expression levels were significantly increased in PMN-MDSCs in later pregnancy compared to those in early pregnancy and non-pregnant females. Female mice lacking Olfm4 in myeloid cells mated with wild-type males showed FGR during pregnancy, with a decreased placental PMN-MDSCs population and expression of growth-promoting factors (GPFs) from placental PMN-MDSCs. Galectin-3 (Gal-3) stimulated the OLFM4-mediated secretion of GPFs by placental PMN-MDSCs. Moreover, GPF regulation via OLFM4 in placental PMN-MDSCs was mediated via hypoxia inducible factor-1α (HIF-1α). Notably, the offspring of mothers lacking Olfm4 exhibited intestinal inflammation and were susceptible to NEC. Additionally, OLFM4 expression decreased in placental PMN-MDSCs from pregnancies with FGR and was negatively correlated with neonatal morbidity. These results revealed that placental PMN-MDSCs contributed to fetal development and ameliorate newborn intestinal inflammation.


Asunto(s)
Retardo del Crecimiento Fetal , Células Supresoras de Origen Mieloide , Placenta , Animales , Femenino , Embarazo , Humanos , Placenta/inmunología , Placenta/metabolismo , Recién Nacido , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Retardo del Crecimiento Fetal/inmunología , Ratones , Ratones Noqueados , Enterocolitis Necrotizante/inmunología , Enterocolitis Necrotizante/metabolismo , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos/genética , Ratones Endogámicos C57BL , Masculino , Galectinas/metabolismo , Galectinas/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Intestinos/inmunología , Intestinos/patología
3.
Oncogene ; 41(22): 3131-3150, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35487976

RESUMEN

Chronic inflammatory bowel disease (IBD) is strongly associated with the development of colitis-associated tumorigenesis (CAT). Despite recent advances in the understanding of polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) responses in cancer, the mechanisms of these cells during this process remain largely uncharacterized. Here, we discovered a glycoprotein, olfactomedin-4 (OLFM4), was highly expressed in PMN-MDSCs from colitis to colorectal cancer (CRC), and its expression level and PMN-MDSC population positively correlated with the progression of IBD to CRC. Moreover, mice lacking OLFM4 in myeloid cells showed poor recruitment of PMN-MDSCs, impaired intestinal homeostasis, and delayed development from IBD to CRC, and increased response to anti-PD1 therapy. The main mechanism of OLFM4-mediated PMN-MDSC activity involved the NF-κB/PTGS2 pathway, through the binding of LGALS3, a galactoside-binding protein expressed on PMN-MDSCs. Our results showed that the OLFM4/NF-κB/PTGS2 pathway promoted PMN-MDSC recruitment, which played an essential role in the maintenance of intestinal homeostasis, but showed resistance to anti-PD1 therapy in CRC.


Asunto(s)
Colitis , Neoplasias Colorrectales , Glicoproteínas/metabolismo , Enfermedades Inflamatorias del Intestino , Células Supresoras de Origen Mieloide , Animales , Colitis/genética , Colitis/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Ciclooxigenasa 2/metabolismo , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Ratones , Células Supresoras de Origen Mieloide/metabolismo , FN-kappa B/metabolismo
4.
J Leukoc Biol ; 110(6): 1143-1161, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34636072

RESUMEN

Elimination of the posttraumatic inflammatory response and recovery of homeostasis are crucial for the positive prognosis of trauma patients. Myeloid-derived suppressor cells (MDSCs) are known to play a regulatory role in the posttraumatic immune response in mice, but their induction source and involved potential mechanism are poorly understood. Here, we report that polymorphonuclear MDSCs (PMN-MDSCs) are activated after trauma and are closely associated with the progression of the posttraumatic inflammatory response. In humans, lectin-type oxidized LDL receptor 1 (LOX1) was used to specifically characterize LOX1+ PMN-MDSCs. Trauma patients showed high intracellular reactive oxygen species (ROS) production, as well as activation of LOX1+ PMN-MDSCs. These MDSCs contribute to the anti-inflammatory immune response by regulating the Treg/Th17 and Th2/Th1 balances after trauma, increasing the levels of anti-inflammatory factors, and decreasing the levels of proinflammatory factors. The number of LOX1+ PMN-MDSCs was positively correlated with the positive clinical prognosis of trauma patients with infection. Activation of LOX1+ PMN-MDSCs is mediated by NF-κB signal, and TGF-ß1 may be as an important inducer for LOX1+ PMN-MDSCs in the posttraumatic cytokine environment. In a pseudofracture trauma mouse model, we also observed the activation of PMN-MDSCs, accompanying high levels of intracellular ROS production, NF-κB phosphorylation, and changes in the inflammatory environment, in particularly by regulating the Treg/Th17 and Th2/Th1 balance. And more significantly, posttraumatic inflammation was alleviated in mice after transferring trauma-derived PMN-MDSCs, but aggravated after injecting with Gr1 agonistic antibody. These findings provide evidence for the specific role of PMN-MDSCs in the regulation of posttraumatic inflammation.


Asunto(s)
Inflamación/inmunología , Células Supresoras de Origen Mieloide/inmunología , Neutrófilos/inmunología , Heridas y Lesiones/inmunología , Animales , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
5.
Cell Mol Immunol ; 18(7): 1692-1707, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34099889

RESUMEN

The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy. Although studies have shown that myeloid-derived suppressor cells (MDSCs) play an important role in maintaining feto-maternal tolerance, little is known about the role of MDSCs in pregnancies with intrauterine growth retardation (IUGR). Here, we reported that the activation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) during pregnancy was closely associated with fetal growth. In humans, class E scavenger receptor 1 (SR-E1), a distinct marker for human PMN-MDSCs, was used to investigate PMN-MDSC function during pregnancy. Continuous activation of SR-E1+ PMN-MDSCs was observed in all stages of pregnancy, accompanied by high cellular levels of ROS and arginase-1 activity, mediated through STAT6 signaling. However, SR-E1+ PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity, lower arginase-1 activity and ROS levels, and decreased STAT6 phosphorylation level, which were accompanied by an increase in inflammatory factors, compared with those in normal pregnancies. Moreover, the population of SR-E1+ PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR. In mice, decreases in cell population, suppressive activity, target expression levels, and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies, which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice. Interestingly, the growth-promoting factors (GPFs) secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development. These findings collectively support that PMN-MDSCs have another new role in pregnancy, which can improve adverse neonatal outcomes.


Asunto(s)
Células Supresoras de Origen Mieloide , Animales , Femenino , Desarrollo Fetal , Tolerancia Inmunológica , Ratones , Placenta , Embarazo , Transducción de Señal
6.
Front Immunol ; 12: 641874, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33828553

RESUMEN

The endothelin-A receptor antagonist BQ123 is an effective treatment agent for hypertension and obese cardiomyopathy. However, the role of BQ123 in controlling acute inflammatory diseases and its underlying mechanisms are not well understood. Here, we showed that BQ123 activated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice and that the IL13/STAT6/Arg1 signaling pathway is involved in this process. Importantly, both treatment with BQ123 and the transfer of BQ123-induced PMN-MDSCs (BQ123-MDSCs) were effective in relieving inflammation, including dextran sulfate sodium (DSS)-induced colitis, papain-induced pneumonia, and concanavalin A (ConA)-induced hepatitis, in mice. The treatment effects were mediated by the attenuation of the inflammation associated with the accumulation of PMN-MDSCs in the colon, lung, and liver. However, concurrent injection of Gr1 agonistic antibody with BQ123 induced PMN-MDSC aggravated the observed acute inflammation. Interestingly, no remission of inflammation was observed in Rag2 knockout mice administered BQ123-MDSCs, but co-injection with CD3+ T cells significantly relieved acute inflammation. In summary, BQ123-induced PMN-MDSCs attenuated acute inflammation in a T cell-dependent manner, providing a novel potential strategy to prevent the occurrence of acute inflammation.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Colitis/tratamiento farmacológico , Antagonistas de los Receptores de la Endotelina A/farmacología , Granulocitos/inmunología , Células Supresoras de Origen Mieloide/inmunología , Péptidos Cíclicos/farmacología , Neumonía/tratamiento farmacológico , Linfocitos T/inmunología , Enfermedad Aguda , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Colitis/inducido químicamente , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Neumonía/inducido químicamente , Neumonía/inmunología
7.
Eur J Immunol ; 51(5): 1110-1125, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547649

RESUMEN

Intestinal trefoil factor 3 (TFF3) plays an important role in repairing the intestinal mucosa. However, the detailed mechanism regarding immune regulation by TFF3 is not well defined. Here, we reported that treatment of mouse BM cells and human peripheral blood mononuclear cells from healthy volunteers with TFF3 activated polymorphnuclear myeloid-derived suppressor cells (PMN-MDSCs) in vitro. We also found that prostaglandin E2 is a major TFF3-mediated MDSC target, and that NF-κB/COX2 signaling was involved in this process. Moreover, TFF3 treatment or transfer of TFF3-derived PMN-MDSCs (TFF3-MDSCs) to experimental necrotizing enterocolitis (NEC) mice caused PMN-MDSC accumulation in the lamina propria (LP), which was associated with decreased intestinal inflammation, permeability, bacterial loading, and prolonged survival. Interestingly, no NEC severity remission was observed in Rag1 KO mice that were given TFF3-MDSCs, but coinjection with CD4+ T cells significantly relieved NEC inflammation. Overall, TFF3 mediates the NF-κB/COX2 pathway to regulate PMN-MDSC activation and attenuates NEC in a T-cell-dependent manner, which suggests a novel mechanism in preventing NEC occurrence.


Asunto(s)
Ciclooxigenasa 2/metabolismo , Enterocolitis Necrotizante/etiología , Enterocolitis Necrotizante/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , FN-kappa B/metabolismo , Neutrófilos/metabolismo , Transducción de Señal , Factor Trefoil-3/genética , Animales , Animales Recién Nacidos , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Enterocolitis Necrotizante/patología , Regulación de la Expresión Génica , Humanos , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones , Ratones Noqueados , Células Supresoras de Origen Mieloide/inmunología , Neutrófilos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor Trefoil-3/metabolismo
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