Myeloid-derived suppressor cells in non-neoplastic inflamed organs

Abstract Background Myeloid-derived suppressor cells (MDSCs) are a highly heterogeneous population of immature myeloid cells with immunosuppressive function. Although their function in tumor-bearing conditions is well studied, less is known about the role of MDSCs in various organs under non-neoplastic inflammatory conditions. Main body MDSCs are divided into two subpopulations, G-MDSCs and M-MDSCs, and their distribution varies between organs. MDSCs negatively control inflammation in inflamed organs such as the lungs, joints, liver, kidneys, intestines, central nervous system (CNS), and eyes by suppressing T cells and myeloid cells. MDSCs also regulate fibrosis in the lungs, liver, and kidneys and help repair CNS injuries. MDSCs in organs are plastic and can differentiate into osteoclasts and tolerogenic dendritic cells according to the microenvironment under non-neoplastic inflammatory conditions. Conclusion This article summarizes recent findings about MDSCs under inflammatory conditions, especially with respect to their function and differentiation in specific organs

Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice

Background Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a sometimes life-threatening complication in RA patients. SKG mice develop not only arthritis but also an ILD resembling RA-ILD. We previously reported that tofacitinib, a JAK inhibitor, facilitates the expansion of myeloid-derived suppressor cells (MDSCs) and ameliorates arthritis in SKG mice. The aim of this study was to elucidate the effect of tofacitinib on the ILD in SKG mice. Methods We assessed the effect of tofacitinib on the zymosan (Zym)-induced ILD in SKG mice histologically and examined the cells infiltrating the lung by flow cytometry. The effects of lung MDSCs on T cell proliferation and Th17 cell differentiation were assessed in vitro. We also evaluated the effects of tofacitinib on MDSCs and dendritic cells in vitro. Results Tofacitinib significantly suppressed the progression of ILD compared to the control SKG mice. The MDSCs were increased, while Th17 cells, group 1 innate lymphoid cells (ILC1s), and GM-CSF+ILCs were decreased in the lungs of tofacitinib-treated mice. MDSCs isolated from the inflamed lungs suppressed T cell proliferation and Th17 cell differentiation in vitro. Tofacitinib promoted MDSC expansion and suppressed bone marrow-derived dendritic cell (BMDC) differentiation in vitro. Conclusion Tofacitinib facilitates the expansion of MDSCs in the lung and ameliorates ILD in SKG mice

3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation

Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA

Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice

Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4(+) T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G(+) granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4(+) T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4(+) T and Th17 cells in the spleen were lowest in mice treated with the combination therapy. Thus, combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4(+) T cell proliferation and Th17 differentiation. These results suggest the combination of rapamycin and DON may be a potential novel therapy for arthritis

Segregation in the urban space of Soacha Transmilenio as an integrating tool?

La movilidad cotidiana es un factor que puede dificultar aún más el acceso de la población menos favorecida a las actividades diarias, principalmente trabajo y estudio. La investigación se realiza a partir del estudio de caso de fronteras sociourbanas en áreas residenciales populares metropolitanas para entender los factores de segregación y exclusión que se dan en estos territorios. Se realizó un análisis de la situación y la relación que tiene la movilidad cotidiana con la segregación socioespacial, tomando el municipio de Soacha en Cundinamarca, conformado por población de bajos ingresos y que se encuentra conurbado con la capital del país. El estudio se efectuó a partir de encuestas a los residentes del Macroproyecto Ciudad Verde (Soacha) y entrevistas a los actores clave del proyecto (administradores de los conjuntos residenciales). En una primera etapa se realizaron encuestas para conocer la forma en que los residentes de Ciudad Verde se desplazaban diariamente antes de la implementación de la extensión hasta Soacha de Transmilenio; en una segunda etapa se preguntó si los desplazamientos diarios habían mejorado con la entrada en funcionamiento del Transmilenio hasta Soacha, con el fin de indagar hasta qué punto este sistema ha servido como una herramienta integradoraDaily mobility is a factor that can further hinder the access of disadvantaged populations to daily activities, mainly work and study. Research is conducted from case study in sociourban borders metropolitan popular residential areas to understand the factors of segregation and exclusion that occur in these territories. An analysis of the situation and the relationship of the daily mobility with the socio-spatial segregation was conducted, taking Soacha’s town in Cundinamarca, made up of low-income population and is conurbation with the capital. The study was conducted from surveys to residents of Green City’s macro-project (Soacha) and interviews with key project stakeholders (administrators of residential complexes). In a first stage, surveys were conducted to know how that Green City residents moved daily before the implementation of the extension of Transmilenio to Soacha; in a second stage, there was the matter of seeing if commuting had improved with the entry into operation of Transmilenio to Soacha, in order to investigate to what extent this system has served as an integrating too