The Trypanosoma brucei-Derived Ketoacids, Indole Pyruvate and Hydroxyphenylpyruvate, Induce HO-1 Expression and Suppress Inflammatory Responses in Human Dendritic Cells

The extracellular parasite and causative agent of African sleeping sickness Trypanosoma brucei (T. brucei) has evolved a number of strategies to avoid immune detection in the host. One recently described mechanism involves the conversion of host-derived amino acids to aromatic ketoacids, which are detected at relatively high concentrations in the bloodstream of infected individuals. These ketoacids have been shown to directly suppress inflammatory responses in murine immune cells, as well as acting as potent inducers of the stress response enzyme, heme oxygenase 1 (HO-1), which has proven anti-inflammatory properties. The aim of this study was to investigate the immunomodulatory properties of the T. brucei-derived ketoacids in primary human immune cells and further examine their potential as a therapy for inflammatory diseases. We report that the T. brucei-derived ketoacids, indole pyruvate (IP) and hydroxyphenylpyruvate (HPP), induce HO-1 expression through Nrf2 activation in human dendritic cells (DC). They also limit DC maturation and suppress the production of pro-inflammatory cytokines, which, in turn, leads to a reduced capacity to differentiate adaptive CD4+ T cells. Furthermore, the ketoacids are capable of modulating DC cellular metabolism and suppressing the inflammatory profile of cells isolated from patients with inflammatory bowel disease. This study therefore not only provides further evidence of the immune-evasion mechanisms employed by T. brucei, but also supports further exploration of this new class of HO-1 inducers as potential therapeutics for the treatment of inflammatory conditions.

TNF-α, IL-1β, MMP-8 Crevicular Profile in Patients with Chronic Kidney Disease and Periodontitis

Increasing evidence sustains the potential of periodontitis as a risk factor for chronic kidney disease (CKD). Our study aimed to analyze several periodontal specific inflammatory biomarkers within the gingival crevicular fluid (GCF) of patients with CKD, compared to patients with normal kidney function, providing an inflammatory profile of the dialysis patient. The study comprised 79 patients divided into: group 1 (59 subjects with periodontitis and CKD) and group 2 (20 patients with periodontitis, without other systemic conditions). Clinical diagnosis was performed via dental and periodontal examination. GCF samples were collected from each patient, and the levels of TNF-α, IL-1β and MMP-8 were determined by using ELISA assay. In group 1, the average values were: 22.85 ± 5.87 pg/mL for TNF-α, 33.00 ± 39.68 pg/mL for IL-1β and 18.80 ± 27.75 ng/mL for MMP-8. In group 2, the mean values were: 2.10 ± 1.34 pg/mL for TNF-α, 0.71 ± 2.42 pg/mL for IL-1β and 5.35 ± 0.37 ng/mL for MMP-8. Statistical analysis revealed significant differences between groups as referring to all three biomarkers and, TNF-α and MMP-8, in certain stages of periodontitis. The level of TNF-α, IL-1β and MMP-8 points out the increased inflammatory status of the dialysis patient with PD, supporting the mutual connection of the two pathologies.

Morphea Profunda with Tertiary Lymphoid Follicles: Description of Two Cases and Review of the Literature

Morphea profunda or subcutaneous (deep) morphea is a variant of localized morphea, characterized by one or more ill-defined, deep sclerotic plaque. Preferential sites are the abdomen, trunk, sacral area, or extremities. The presence of hyperplastic lymphoid follicles in the context of the sclerotic bands of morphea is rarely described. Localized scleroderma is sustained by a profibrotic inflammatory profile. Transforming growth factor-β (TGF-β), an imbalance between functional subclasses of T-lymphocytes (innate immune cells) has a role in activate collagen deposition. In this case report, we present two cases of morphea profunda with lymphoid follicular hyperplasia. A systematic review of the literature on the pathophysiology of localized scleroderma is also presented, with particular reference to the presence of lymphoid structures.

Antinociceptive and anti-inflammatory activities of Hymenaea martiana Hayne (Fabaceae) in mice

Hymenaea martiana is a species popularly known in Northeastern Brazil as “jatobá” and used in folk medicine to treat pain and inflammation. The aim of this work was to evaluate the antinociceptive and anti-inflammatory activity of H. martiana. In the present study, we carried out an investigation about the effects of the crude ethanolic extract (Hm-EtOH) and the ethyl acetate fraction (Hm-AcOEt) in models of nociception and inflammation in mice. Chemical (acetic acid-induced writhing and formalin) and thermal stimuli (hot plate) were used for the evaluation of antinociceptive activity, while for the anti-inflammatory profile paw edema induced by carrageenan was used, along with leukocyte migration to the peritoneal cavity. The presence of the flavonoid astilbin in the samples was characterized through HPLC-DAD-MS analysis. Hm-EtOH and Hm-AcOEt (100, 200 and 400 mg.kg-1, i.p.) significantly reduced the number of abdominal contortions and decreased the paw licking time in the formalin test. In the hot plate, the extract increased the latency time of animals. Hm-EtOH and Hm-AcOEt inhibited significantly the increase in the edema after the administration of carrageenan. Hm-EtOH and Hm-AcOEt inhibited leukocyte migration in the peritonitis test. HPLC-DAD-MS analysis of Hm-EtOH and Hm-AcOEt revealed the presence of the flavonoid astilbin in the samples. According to the results of this study, both Hm-EtOH and Hm-AcOEt have antinociceptive and anti-inflammatory activities, which could be related with the presence of flavonoid in the extracts. The results reinforce the popular use of this plant.

Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING detects bacteria by directly recognizing cyclic dinucleotides or indirectly by bacterial genomic DNA sensing through the cyclic GMP-AMP synthase (cGAS). Upon activation, STING triggers a plethora of powerful signaling pathways, including the production of type I interferons and proinflammatory cytokines. STING activation has also been associated with the induction of endoplasmic reticulum (ER) stress and the associated inflammatory responses. Recent reports indicate that STING-dependent pathways participate in the metabolic reprogramming of macrophages and contribute to the establishment and maintenance of a robust inflammatory profile. The induction of this inflammatory state is typically antimicrobial and related to pathogen clearance. However, depending on the infection, STING-mediated immune responses can be detrimental to the host, facilitating bacterial survival, indicating an intricate balance between immune signaling and inflammation during bacterial infections. In this paper, we review recent insights regarding the role of STING in inducing an inflammatory profile upon intracellular bacterial entry in host cells and discuss the impact of STING signaling on the outcome of infection. Unraveling the STING-mediated inflammatory responses can enable a better understanding of the pathogenesis of certain bacterial diseases and reveal the potential of new antimicrobial therapy.

Aging Aggravates Cachexia in Tumor-Bearing Mice

Background: Cancer is primarily a disease of high age in humans, yet most mouse studies on cancer cachexia are conducted using young adolescent mice. Given that metabolism and muscle function change with age, we hypothesized that aging may affect cachexia progression in mouse models. Methods: We compare tumor and cachexia development in young and old mice of three different strains (C57BL/6J, C57BL/6N, BALB/c) and with two different tumor cell lines (Lewis Lung Cancer, Colon26). Tumor size, body and organ weights, fiber cross-sectional area, circulating cachexia biomarkers, and molecular markers of muscle atrophy and adipose tissue wasting are shown. We correlate inflammatory markers and body weight dependent on age in patients with cancer. Results: We note fundamental differences between mouse strains. Aging aggravates weight loss in LLC-injected C57BL/6J mice, drives it in C57BL/6N mice, and does not influence weight loss in C26-injected BALB/c mice. Glucose tolerance is unchanged in cachectic young and old mice. The stress marker GDF15 is elevated in cachectic BALB/c mice independent of age and increased in old C57BL/6N and J mice. Inflammatory markers correlate significantly with weight loss only in young mice and patients. Conclusions: Aging affects cachexia development and progression in mice in a strain-dependent manner and influences the inflammatory profile in both mice and patients. Age is an important factor to consider for future cachexia studies.

The inflammatory profile of chronic kidney disease patients

Background: Chronic kidney disease is a worldwide public health issue which is associated with an increased risk of end-stage renal failure and cardiovascular disease. Systemic inflammation exists during chronic renal failure. Recent researches have highlighted the pivotal role of inflammation between renal and cardiovascular disease. The aim of our study is to determine the inflammatory profile of the patient suffering from chronic kidney disease and the influence of hemodialysis on this profile. Methods: We carried out a cross sectional study on 93 patients in the Nephrology Department at Hedi Chaker University Hospital, Sfax, South of Tunisia. Among those patients, 72 patients underwent hemodialysis and 21 patients had chronic kidney disease at stage 3. Clinical data and antecedents were collected. Biological samples were taken after informing the patients and taking their consent. Biological data consisted in lipid profile, albumin rate, hemoglobin rate, uric acid concentration and the usual markers of inflammation noting sedimentation rate, C - reactive protein and orosomucoid. Results: Hemodialysis group of the 72 patients had mean hemodialysis vintage of 54.6 ± 43 months. The inflammatory profile was worse in hemodialysis patients compared to chronic kidney disease patients. Both sedimentation rate, C - reactive protein and orosomucoid were higher in hemodialysis group than in chronic kidney disease group with 71 ± 35.3 mm vs. 42.1 ± 15.5 mm (p < 0.05); 14.6 ± 28.7 mg/l vs. 6.7 ± 8 mg/l (p = 0.02); 1.3 ± 0.7g/l vs. 0.9 ± 0.4 g/l (p = 0.01), respectively. Conclusion: Inflammation increases in dialysis patient. It deserves the nephrologist’s consideration in order to minimize its harmful effects. The monitoring of inflammation markers must be integrated into the nephrologist’s medical practice.

Impact of Sex Hormones on Macrophage Responses to Coxiella burnetii

IntroductionQ fever, a zoonosis caused by Coxiella burnetii, affects more males than females despite a similar level of exposure. A protective role of estradiol has been reported in mice, suggesting that sex hormones are involved in C. burnetii infection. We wondered whether the responses of monocytes and monocyte-derived macrophages (MDMs) to C. burnetii are influenced by sex hormones.Materials and MethodsThe bacterial intracellular fate in monocytes was studied using quantitative PCR, and monocyte cytokine production in response to C. burnetii was assessed using qRT-PCR and immunoassays. Before infection, MDMs from males and females were incubated with testosterone and estradiol, respectively.ResultsBacterial uptake and persistence were similar in monocytes from males and females but were slightly increased in male MDMs. The expression of inflammatory genes, including those encoding TNF and CXCL10, was higher in MDMs from females than in MDMs from males infected by C. burnetii. Adding testosterone to male MDMs amplified their immunoregulatory properties, including increased expression of IL10 and TGFB genes and TGF-β production in response to C. burnetii. In contrast, adding estradiol to MDMs from females had no effect on their inflammatory profile.ConclusionThe stronger inflammatory profile of macrophages from females may have a protective role, likely under estrogen control, while testosterone may affect disease progression by promoting an anti-inflammatory response. This finding may have consequences for personalized management of patients with Q fever.

Effect of Lonomia obliqua Venom on Human Neutrophils

The significant incidence of deforestation in South America culminates in the contact of humans with typical forests species. Among these species, one may highlight Lonomia obliqua caterpillar, which, when touched by humans, can poison them through their bristles. Therefore, better acknowledging the mechanisms involved in envenomation caused by Lonomia obliqua caterpillar bristle extract (LOCBE) may contribute to further treatments. Recently, we demonstrated that LOCBE induces a pro-inflammatory profile in endothelial cells; thus, we decided to investigate the effects of LOCBE on human polymorphonuclear neutrophils (PMN), which are the first leukocytes that migrate to the inflammatory focus. Our results showed that treatment with LOCBE induced PMN chemotaxis together with alterations in actin cytoskeleton and focal adhesion kinase (FAK) activation, favoring migration. Concurrently, LOCBE induced PMN adhesion to matrix proteins, such as collagen IV, fibronectin, and fibrinogen. Moreover, we observed that LOCBE attenuated PMN apoptosis and increased reactive oxygen species (ROS) production together with nuclear factor kB (NF-κB) activation—a redox-sensitive transcription factor—as well as interleukin (IL)-1β and IL-8 release. We call attention to the ROS-dependent effect of LOCBE on increased cell migration once an antioxidant treatment reverted it. In summary, we report that LOCBE activates PMN, inducing pro-inflammatory responses modulated by ROS.

Exploring the Diverse Immune and Genetic Landscape of Psoriatic Arthritis

Psoriatic arthritis (PsA) is characterized by delays in diagnosis and a modest effect of treatment in terms of joint response. An understanding of molecular pathomechanisms may aid in developing diagnostic and prognostic models. Genetic susceptibility (e.g., HLA class I genes, IL-23-related genes) can be responsible for the pattern of psoriatic manifestations and affinity for tissue involvement. Gene expression analysis indicates an inflammatory profile that is distinct for PsA, but disparate across tissues. This has clinical implications, as for example, dual blockade of IL-17A and IL-17F can lead to superior clinical effects if there is differential expression of IL-17 receptors in tissues. Structural and functional impairment of barrier tissue, including host-microbiome interactions, may be the source of immune activation. Interplay between different cell populations of innate and adaptive immunity is emerging, potentially providing a link between the transition of skin-to-joint disease. Th17 subsets, IL-17A, IL-17F and IL-23 are crucial in PsA pathogenesis, with both clinical and experimental evidence suggesting a differential molecular landscape in cutaneous and articular compartments.