Reciprocal interference between the NRF2 and LPS signaling pathways on the immune-metabolic phenotype of peritoneal macrophages

The metabolic and immune adaptation to extracellular signals allows macrophages to carry out specialized functions involved in immune protection and tissue homeostasis. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that coordinates cell redox and metabolic responses to stressors. However, the individual and concomitant activation of NRF2 and inflammatory pathways have been poorly investigated in isolated macrophages. We here took advantage of reporter mice for the transcriptional activities of NRF2 and nuclear factor-kB (NF\u3baB), a key transcription factor in inflammation, and observe a persisting reciprocal interference in the response of peritoneal macrophages to the respective activators, tert-Butylhydroquinone (tBHQ) and lipopolysaccharide (LPS). When analyzed separately by gene expression studies, these pathways trigger macrophage-specific metabolic and proliferative target genes that are associated with tBHQ-induced pentose phosphate pathway (PPP) with no proliferative response, and with opposite effects observed with LPS. Importantly, the simultaneous administration of tBHQ + LPS alters the effects of each individual pathway in a target gene-specific manner. In fact, this co-treatment potentiates the effects of tBHQ on the antioxidant enzyme, HMOX1, and the antibacterial enzyme, IRG1, respectively; moreover, the combined treatment reduces tBHQ activity on the glycolytic enzymes, TALDO1 and TKT, and decreases LPS effects on the metabolic enzyme IDH1, the proliferation-related proteins KI67 and PPAT, and the inflammatory cytokines IL-1\u3b2, IL-6, and TNF\u3b1. Altogether, our results show that the activation of NRF2 redirects the metabolic, immune, and proliferative response of peritoneal macrophages to inflammatory signals, with relevant consequences for the pharmacological treatment of diseases that are associated with unopposed inflammatory responses

Sex-Specific Microglial Responses to Glucocerebrosidase Inhibition: Relevance to GBA1-Linked Parkinson’s Disease

Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to stimulation: male microglia tended to have a more pro-inflammatory phenotype, while female microglia showed increased sensitivity to conduritol-B-epoxide (CBE), a small molecule inhibitor of glucocerebrosidase, the enzyme encoded by the GBA1 gene, mutations of which are the major risk factor for Parkinson’s Disease (PD). Interestingly, glucocerebrosidase inhibition particularly impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons, attenuating the sex differences observed in this neuroprotective function. This finding is consistent with the clinical impact of GBA1 mutations, in which the 1.5–2-fold reduced risk of developing idiopathic PD observed in female individuals is lost in the GBA1 carrier population, thus suggesting a sex-specific role for microglia in the etiopathogenesis of PD-GBA1

ER alpha-independent NRF2-mediated immunoregulatory activity of tamoxifen

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGFα and other immune activation genes by ERα- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNFα and IL1β, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion through caspase-1 activation

Studia Lichenologica in Italy. I. New records of red-listed species

We present new data concerning lichen species of the Italian flora and confirm 36 national redlisted species

Mild Systemic Oxidative Stress in the Subclinical Stage of Alzheimer's Disease

Alzheimer's disease (AD) is a late-onset, progressive degenerative disorder that affects mainly the judgment, emotional stability, and memory domains. AD is the outcome of a complex interaction among several factors which are not fully understood yet; nevertheless, it is clear that oxidative stress and inflammatory pathways are among these factors. 65 elderly subjects (42 cognitively intact and 23 with probable Alzheimer's disease) were selected for this study. We evaluated erythrocyte activities of superoxide dismutase, catalase, and glutathione peroxidase as well as plasma levels of total glutathione, alpha-tocopherol, beta-carotene, lycopene, and coenzyme Q10. These antioxidant parameters were confronted with plasmatic levels of protein and lipid oxidation products. Additionally, we measured basal expression of monocyte HLA-DR and CD-11b, as well as monocyte production of cytokines IL1-alpha, IL-6, and TNF-alpha. AD patients presented lower plasmatic levels of alpha-tocopherol when compared to control ones and also higher basal monocyte HLA-DR expression associated with higher IL-1 alpha production when stimulated by LPS. These findings support the inflammatory theory of AD and point out that this disease is associated with a higher basal activation of circulating monocytes that may be a result of alpha-tocopherol stock depletion.Univ São Paulo, Inst Quim, BR-05508900 São Paulo, BrazilUNIFESP, Inst Ciencias Ambientais Quim Farmaceut, BR-09972270 Diadema, SP, BrazilFMABC, Dept Hematol & Oncol, BR-09060650 Santo Andre, SP, BrazilUniversidade Federal de São Paulo, Dept Med, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med Prevent, BR-04021001 São Paulo, BrazilUNIFESP, Inst Ciencias Ambientais Quim Farmaceut, BR-09972270 Diadema, SP, BrazilUniversidade Federal de São Paulo, Dept Med, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med Prevent, BR-04021001 São Paulo, BrazilWeb of Scienc

The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis

<p>Abstract</p> <p>Background</p> <p>CD4⁺CD25^highregulatory T (T_Reg) cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of T_Regcell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of T_Regcells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP) patients, and to correlate with measures of T cell activation.</p> <p>Results</p> <p>We were able to confirm that HTLV-I drives activation, spontaneous IFNγ production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4⁺T_Regcells (CD4⁺CD25^highT cells) in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4⁺T_Regcells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127^lowT_Regcells in healthy control subjects. Finally, the proportion of CD127^lowT_Regcells correlated inversely with HTLV-1 proviral load.</p> <p>Conclusion</p> <p>Taken together, the results suggest that T_Regcells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4⁺T cells, in particular those expressing the CD25^highCD127^lowphenotype. T_Regcells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.</p

Testing an expanded set of sustainable forest management indicators in Mediterranean coppice area

Although coppice forests represent a significant part of the European forest area, especially across southern Countries, they received little attention within the Sustainable Forest Management (SFM) processes and scenarios, whose guidelines have been mainly designed to high forests and national scale. In order to obtain “tailored” information on the degree of sustainability of coppices on the scale of the stand, we evaluated (i) whether the main coppice management options result in different responses of the SFM indicators, and (ii) the degree to which the considered SFM indicators were appropriate in their application at stand level. The study considered three different management options (Traditional Coppice TC, coppice under Natural Evolution NE, and coppice under Conversion to high forest by means of periodical thinning CO). In each of the 43 plots considered in the study, which covered three different European Forest Types, we applied a set of eighteen “consolidated” SFM indicators, covering all the six SFM Criteria (FOREST EUROPE, 2020) and, additionally, tested other sixteen novel indicators shaped for agamic forests and/or applicable at stand level. Results confirmed that several consolidated indicators related to resources status (Growing stock and Carbon stock), health (Defoliation and Forest damage), and socio-economic functions (Net revenue, Energy and Accessibility) were highly appropriate for evaluating the sustainability of coppice at stand level. In addition, some novel indicators related to resources status (Total above ground tree biomass), health (Stand growth) and protective functions (Overstorey cover and Understorey cover) proved to be highly appropriate and able to support the information obtained by the consolidated ones. As a consequence, a subset of consolidated SFM indicators, complemented with the most appropriate novel ones, may represent a valid option to support the evaluation of coppice sustainability at stand level. An integrated analysis of the SFM indicators showed that NE and CO display significant higher environmental performances as compared with TC. In addition, CO has positive effects also on socio-economic issues, while TC -which is an important cultural heritage and a silvicultural option that may help to keep local communities engaged in forestry – combines high wood harvesting rates with dense understory cover. Overall, each of the three management options showed specific sustainability values; as a consequence, their coexistence at a local scale and in accordance with the specific environmental conditions and the social-economic context, is greatly recommended since it may fulfill a wider array of sustainability issues

Testing an expanded set of sustainable forest management indicators in Mediterranean coppice area

Although coppice forests represent a significant part of the European forest area, especially across southern Countries, they received little attention within the Sustainable Forest Management (SFM) processes and scenarios, whose guidelines have been mainly designed to high forests and national scale. In order to obtain “tailored” information on the degree of sustainability of coppices on the scale of the stand, we evaluated (i) whether the main coppice management options result in different responses of the SFM indicators, and (ii) the degree to which the considered SFM indicators were appropriate in their application at stand level. The study considered three different management options (Traditional Coppice TC, coppice under Natural Evolution NE, and coppice under Conversion to high forest by means of periodical thinning CO). In each of the 43 plots considered in the study, which covered three different European Forest Types, we applied a set of eighteen “consolidated” SFM indicators, covering all the six SFM Criteria (FOREST EUROPE, 2020) and, additionally, tested other sixteen novel indicators shaped for agamic forests and/or applicable at stand level. Results confirmed that several consolidated indicators related to resources status (Growing stock and Carbon stock), health (Defoliation and Forest damage), and socio-economic functions (Net revenue, Energy and Accessibility) were highly appropriate for evaluating the sustainability of coppice at stand level. In addition, some novel indicators related to resources status (Total above ground tree biomass), health (Stand growth) and protective functions (Overstorey cover and Understorey cover) proved to be highly appropriate and able to support the information obtained by the consolidated ones. As a consequence, a subset of consolidated SFM indicators, complemented with the most appropriate novel ones, may represent a valid option to support the evaluation of coppice sustainability at stand level. An integrated analysis of the SFM indicators showed that NE and CO display significant higher environmental performances as compared with TC. In addition, CO has positive effects also on socio-economic issues, while TC -which is an important cultural heritage and a silvicultural option that may help to keep local communities engaged in forestry – combines high wood harvesting rates with dense understory cover. Overall, each of the three management options showed specific sustainability values; as a consequence, their coexistence at a local scale and in accordance with the specific environmental conditions and the social-economic context, is greatly recommended since it may fulfill a wider array of sustainability issue

A test on Ellenberg indicator values in the Mediterranean evergreen woods (Quercetea ilicis)

The consistency and reliability of Ellenberg’s indicator values (Eiv) as ecological descriptors of the Mediterranean evergreen vegetation ascribed to the phytosociological class Quercetea ilicis have been checked on a set of 859 phytosociological relevés × 699 species. Diagnostic species were identified through a Twinspan analysis and their Eiv analyzed and related to the following independent variables: (1) annual mean temperatures, (2) annual rainfall. The results provided interesting insights to disentangle the current syntaxonomical framework at the alliance level demonstrating the usefulness of ecological indicator values to test the efficiency and predictivity of the phytosociological classification