ChemR23 is a G protein-coupled receptor that is triggered by two ligands, the peptide chemerin and the eicosapentaenoic acid-derived lipid mediator resolvin E1 (RvE1). Chemerin acts as a ...chemoattractant for monocytes and macrophages, whereas RvE1 promotes resolution of inflammation-inducing macrophage phagocytosis of apoptotic neutrophils. Although ChemR23-mediated signaling plays a role in mononuclear cell migration to inflamed tissue, as well as in the resolution of inflammation, its regulation in different polarization states of macrophages is largely unknown. We analyzed the expression and function of ChemR23 in monocytes and differently activated human primary macrophages. Using 5' RACE, we identified three transcription start sites and several splice variants of ChemR23 in both monocytes and macrophages. Although the promoters P1 and P3 are used equally in unpolarized macrophages, stimulation with LPS or IFN-γ leads to increased transcription from P3 in inflammatory M1 macrophages. Such ChemR23-expressing M1 macrophages are chemotactic to chemerin, whereas M2 macrophages not expressing ChemR23 surface receptor are not. Repolarization of ChemR23-expressing M1 macrophages with 10 nM RvE1 increases IL-10 transcription and phagocytosis of microbial particles, leading to a resolution-type macrophage distinct from the M2 phenotype. These results show that ChemR23 is tightly regulated in response to inflammatory and anti-inflammatory stimuli. The restricted expression of ChemR23 in naive and M1 macrophages supports the role of ChemR23 in the attraction of macrophages to inflamed tissue by chemerin and in the initiation of resolution of inflammation through RvE1-mediated repolarization of human M1 macrophages toward resolution-type macrophages.
Acute lung injury (ALI) initiates protective responses involving genes downstream of the Nrf2 (Nfe2l2) transcription factor, including heme oxygenase-1 (HO-1), which stimulates mitochondrial ...biogenesis and related anti-inflammatory processes. We examined mitochondrial biogenesis during Staphylococcus aureus pneumonia in mice and the effect of Nrf2 deficiency on lung mitochondrial biogenesis and resolution of lung inflammation. S. aureus pneumonia established by nasal insufflation of live bacteria was studied in mitochondrial reporter (mt-COX8-GFP) mice, wild-type (WT) mice, and Nrf2−/− mice. Bronchoalveolar lavage, wet/dry ratios, real-time RT-PCR and Western analysis, immunohistochemistry, and fluorescence microscopy were performed on the lung at 0, 6, 24, and 48h. The mice survived S. aureus inoculations at 5×108 CFU despite diffuse lung inflammation and edema, but the Nrf2−/− lung showed increased ALI. In mt-COX8-GFP mice, mitochondrial fluorescence was enhanced in bronchial and alveolar type II (AT2) epithelial cells. WT mice displayed rapid HO-1 upregulation and lower proinflammatory TNF-α, IL-1β, and CCL2 and, especially in AT2 cells, higher anti-inflammatory IL-10 and suppressor of cytokine signaling-3 than Nrf2−/− mice. In the alveolar region, WT but not Nrf2−/− mice showed strongly induced nuclear respiratory factor-1, PGC-1α, mitochondrial transcription factor-A, SOD2, Bnip3, mtDNA copy number, and citrate synthase. These findings indicate that S. aureus pneumonia induces Nrf2-dependent mitochondrial biogenesis in the alveolar region, mainly in AT2 cells. Absence of Nrf2 suppresses the alveolar transcriptional network for mitochondrial biogenesis and anti-inflammation, which worsens ALI. The findings link redox activation of mitochondrial biogenesis to ALI resolution.
► Staphylococcus aureus pneumonia induces alveolar mitochondrial biogenesis in mice. Nrf2−/− mice show impaired lung mitochondrial biogenesis compared to WT mice. ► Type II cells are a main site of Nrf2-regulated alveolar mitochondrial biogenesis. ► Nrf2−/− mice have low type II cell anti-inflammatory IL-10 and SOCS3 responses. ► Nrf2 links alveolar mitochondrial biogenesis to local IL-10 and SOCS3 synthesis.
Non-typhoidal Salmonella serotypes (NTS) cause a self-limited gastroenteritis in immunocompetent individuals, while children with severe Plasmodium falciparum malaria can develop a life-threatening ...disseminated infection. This co-infection is a major source of child mortality in sub-Saharan Africa. However, the mechanisms by which malaria contributes to increased risk of NTS bacteremia are incompletely understood. Here, we report that in a mouse co-infection model, malaria parasite infection blunts inflammatory responses to NTS, leading to decreased inflammatory pathology and increased systemic bacterial colonization. Blunting of NTS-induced inflammatory responses required induction of IL-10 by the parasites. In the absence of malaria parasite infection, administration of recombinant IL-10 together with induction of anemia had an additive effect on systemic bacterial colonization. Mice that were conditionally deficient for either myeloid cell IL-10 production or myeloid cell expression of IL-10 receptor were better able to control systemic Salmonella infection, suggesting that phagocytic cells are both producers and targets of malaria parasite-induced IL-10. Thus, IL-10 produced during the immune response to malaria increases susceptibility to disseminated NTS infection by suppressing the ability of myeloid cells, most likely macrophages, to control bacterial infection.
Abstract
Background
From December 2019 to February 2020, 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious outbreak of coronavirus disease 2019 (COVID-19) in ...Wuhan, China. Related clinical features are needed.
Methods
We reviewed 69 patients who were hospitalized in Union hospital in Wuhan between 16 January and 29 January 2020. All patients were confirmed to be infected with SARS-CoV-2, and the final date of follow-up was 4 February 2020.
Results
The median age of 69 enrolled patients was 42.0 years (interquartile range 35.0–62.0), and 32 patients (46%) were men. The most common symptoms were fever (60 87%), cough (38 55%), and fatigue (29 42%). Most patients received antiviral therapy (66 98.5% of 67 patients) and antibiotic therapy (66 98.5% of 67 patients). As of 4 February 2020, 18 (26.9%) of 67 patients had been discharged, and 5 patients had died, with a mortality rate of 7.5%. According to the lowest SpO2 during admission, cases were divided into the SpO2 ≥ 90% group (n = 55) and the SpO2 < 90% group (n = 14). All 5 deaths occurred in the SpO2 < 90% group. Compared with SpO2 ≥ 90% group, patients of the SpO2 < 90% group were older and showed more comorbidities and higher plasma levels of interleukin (IL) 6, IL10, lactate dehydrogenase, and C reactive protein. Arbidol treatment showed tendency to improve the discharging rate and decrease the mortality rate.
Conclusions
COVID-19 appears to show frequent fever, dry cough, and increase of inflammatory cytokines, and induced a mortality rate of 7.5%. Older patients or those with underlying comorbidities are at higher risk of death.
In this retrospective case series that included 69 adults in Wuhan, 29% of patients showed dyspnea and 20% of cases showed SpO2 < 90%. Patients with SpO2 < 90% had a significantly higher risk of death. Abidol showed initial therapeutic effect.
Lung epithelial cells can influence immune responses to airway allergens. Airway epithelial cells also undergo apoptosis after encountering environmental allergens; yet, relatively little is known ...about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells. Administration of exogenous IL-10 'rescued' the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens.
Macrophages respond to LPS by the rapid activation of proinflammatory cytokines that serve to initiate host defense against microbial invasion. To prevent injury to the host from excess production of ...these cytokines, IL-10 is up-regulated to feedback inhibit the proinflammatory response. However, the molecular events responsible for LPS-induced up-regulation of IL-10 remain to be elucidated. In this study, we provide evidence that production of and signaling by type I IFN is required for LPS-induced IL-10 up-regulation. In addition, we demonstrate that defect in type I IFN production and signaling results in a trend toward LPS-mediated superinduction of proinflammatory genes and cytokines in bone marrow-derived macrophages. Our findings suggest a novel anti-inflammatory role for the type I IFN production and signaling pathway in regulating LPS response in bone marrow-derived macrophages.
Gene therapy for the control of pain has, to date, targeted neurons. However, recent evidence supports that spinal cord glia are critical to the creation and maintenance of pain facilitation through ...the release of proinflammatory cytokines. Because of the ability of interleukin‐10 (IL‐10) to suppress proinflammatory cytokines, we tested whether an adenoviral vector encoding human IL‐10 (AD‐h‐IL10) would block and reverse pain facilitation. Three pain models were examined, all of which are mediated by spinal pro‐inflammatory cytokines. Acute intrathecal administration of rat IL‐10 protein itself briefly reversed chronic constriction injury‐induced mechanical allodynia and thermal hyperalgesia. The transient reversal caused by IL‐10 protein paralleled the half‐life of human IL‐10 protein in the intrathecal space (t1/2 ∼ 2 h). IL‐10 gene therapy both prevented and reversed thermal hyperalgesia and mechanical allodynia, without affecting basal responses to thermal or mechanical stimuli. Extra‐territorial, as well as territorial, pain changes were reversed by this treatment. Intrathecal AD‐h‐IL10 injected over lumbosacral spinal cord led to elevated lumbosacral cerebrospinal fluid (CSF) levels of human IL‐10, with far less human IL‐10 observed in cervical CSF. In keeping with IL‐10's known anti‐inflammatory actions, AD‐h‐IL10 lowered CSF levels of IL‐1, relative to control AD. These studies support that this gene therapy approach provides an alternative to neuronally focused drug and gene therapies for clinical pain control.
CD9 was recently identified as a marker of murine IL-10-competent regulatory B cells. Functional impairments or defects in CD9
IL-10-secreting regulatory B cells are associated with enhanced ...asthma-like inflammation and airway hyperresponsiveness. In mouse models, all asthma-related features can be abrogated by CD9
B cell adoptive transfer. We aimed herein to decipher the profiles, features, and molecular mechanisms of the regulatory properties of CD9
B cells in human and mouse. The profile of CD9
B cells was analyzed using blood from severe asthmatic patients and normal and asthmatic mice by flow cytometry. The regulatory effects of mouse CD9
B cells on effector T cell death, cell cycle arrest, apoptosis, and mitochondrial depolarization were determined using yellow dye, propidium iodide, Annexin V, and JC-1 staining. MAPK phosphorylation was analyzed by western blotting. Patients with severe asthma and asthmatic mice both harbored less CD19
CD9
B cells, although these cells displayed no defect in their capacity to induce T cell apoptosis. Molecular mechanisms of regulation of CD9
B cells characterized in mouse showed that they induced effector T cell cycle arrest in sub G0/G1, leading to apoptosis in an IL-10-dependent manner. This process occurred through MAPK phosphorylation and activation of both the intrinsic and extrinsic pathways. This study characterizes the molecular mechanisms underlying the regulation of CD9
B cells to induce effector T cell apoptosis in mice and humans via IL-10 secretion. Defects in CD9
B cells in blood from patients with severe asthma reveal new insights into the lack of regulation of inflammation in these patients.
Regulatory B cells (Bregs) producing IL-10 have negative regulatory function. Several studies have shown the important roles for Toll-like receptor 2 (TLR2), TLR4, and TLR9 ligation in the ...development of Bregs. We have reported that Schistosome soluble egg antigen (SEA) induced the production of Bregs. However, it remains unclear whether such activation is via the TLR pathway. The present study showed that IL-10 and TLR4 mRNA expression in spleen B cells of significantly increased in C57BL/10 J mice spleen B cells following SEA stimulation. The level of secreted IL-10 and IL-10+ B cell proportion decreased in spleen B cells derived from TLR4-deficient C57BL/10ScNJ (TLR4-/-) mice following SEA or LPS stimulation compared with C57BL/10 J mice. The CD1dhiCD5+ B cells proportion decreased in spleen B cells of TLR4-/- mice following SEA stimulation compared with control mice. NF-κB, ERK, p38MAPK and JNK signal transduction inhibitors significantly suppressed IL-10 secretion in CD1dhiCD5+ B cells induced by SEA or LPS. The phosphorylation levels of IκBα, p65, ERK, JNK and p38 were increased in CD1dhiCD5+ B cell of C57BL/10 J mice treated with LPS or SEA. In conclusion, this study suggests that TLR4 plays a critical role in Bregs activation induced by SEA. And the TLR4-triggered NF-κB and MAPK pathways activation in CD1dhiCD5+ B cells stimulated with SEA. The findings elucidated the mechanism of SEA induction of CD1dhiCD5+ B cells and helped us to understand the immune regulation during Schistosoma japonicum infection.
•Schistosome soluble egg antigen induces the production of CD1dhiCD5+ Bregs.•The Bregs induced by Schistosome soluble egg antigen depended on the TLR4 pathway.•The activation of Bregs via TLR4 are related with NF-κB and MAPK pathways.
•In rheumatoid arthritis there is an exacerbated up-regulation of IL-10 at the transcriptional level.•Increased IL-10 levels are associated with seropositivity for RF and anti-CCP antibodies.•GCC ...haplotype was associated with higher IL-10 serum levels compared with the ACC and ATA haplotypes in RA patients.•There was no significant association between IL10 haplotypes and risk of RA in a Mexican population.
Interleukin 10 (IL-10) is an immunomodulatory cytokinethat plays a central rolein the pathogenesis of autoimmune diseases. Different studies consistently show increased IL-10 serum levels in rheumatoid arthritis (RA) and it appears to be caused by genetic variants. Three polymorphisms situated at positions −1082, −819 and −592 of IL10 gene and its major haplotypes have been associated with regulating IL10 promoter activity. In this study, we evaluated whether IL10 haplotypes are associated with mRNA expression and IL-10 serum levels as well as susceptibility to RA in a Western Mexican population. A total of 240 RA patients and 240 control subjects (CS) were included. Genotyping of IL10 polymorphisms was performed by PCR and PCR-RFLP, respectively. IL10 mRNA expression was determined by real-time PCR and IL-10 serum levels were measured using an ELISA kit. IL10 mRNA expression was 50-fold higher in RA patients than CS (p<0.001), while IL-10 serum levels did not show differences between groups. However, high IL-10 serum levels were positively related to a higherseropositivityfor rheumatoid factor (FR) and anti-CCP antibodies (p<0.05). No significant differences between the distribution of haplotype frequencies were observed between both study groups, but GCC haplotype was associated with higher IL-10 serum levels compared with the ACC and ATA haplotypes in RA patients (p<0.05). In addition, patients carrying ATA and GCC haplotypes showed higher mRNA expression than ACC (5.4-fold and 8.8-fold, respectively) and surprisingly, this trend was reversed in the controls, although it was not significant. In conclusion, our findings suggest that IL10 (GCC, ACC, and ATA) haplotypes may not be a susceptibility marker for RA in a population from Western Mexico. Nevertheless, independently of the presence of these variants, there is an aberrant overexpression of IL10 gene in RA, and it may play an important role in the pathogenesis of RA.
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