Giant Tophaceous Gout: The Importance of Therapeutic Compliance.

Gout is a metabolic disease resulting from the deposition of monosodium urate crystals in joints, tissues, and organs. Nowadays, the treatment of hyperuricemia is easily accessible and widespread and mainly consists of xanthine oxidase inhibitors and uricosurics. In refractory and advanced cases of gout, amputation surgery may be required. The authors present the case of an 85-year-old man who is non-compliant with hypouricemic medication, has exuberant gout, and has refused amputation surgery several times. The patient went to the emergency department with a triad of acute kidney injuries, acute gout, and poorly controlled pain. Cases of tophaceus gout such as the one presented are very rare nowadays.

Interlimb Coordination during Double Support Phase of Gait in People with and without Stroke.

This study aims to identify differences between participants with and without stroke regarding the ipsilesional and contralesional lower limbs kinematics, kinetics, muscle activity and their variability during double support phase of gait. Eleven post-stroke and thirteen healthy participants performed 10 gait trials at a self-selected speed while being monitored by an optoelectronic motion capture system, two force plates and an electromyographic system. The following outcomes were evaluated during the double support: the time and the joint position; the external mechanical work on the centre of mass; and the relative electromyographic activity. Both, contralesional/ipsilesional and dominant/non-dominant of participants with and without stroke, respectively, were evaluated during double support phase of gait in trailing or leading positions. The average value of each parameter and the coefficient of variation of the 10 trials were analysed. Post-stroke participants present bilateral decreased mechanical work on the centre of mass and increased variability, decreased contralesional knee and ankle flexion in trailing position, increased ipsilesional knee flexion in leading position and increased variability. Increased relative muscle activity was observed in post-stroke participants with decreased variability. Mechanical work on the centre of mass seems to be the most relevant parameter to identify interlimb coordination impairments in post-stroke subjects.

Intramacrophage lipid accumulation compromises T cell responses and is associated with impaired drug therapy against visceral leishmaniasis.

Under perturbing conditions such as infection with Leishmania, a protozoan parasite living within the phagosomes in mammalian macrophages, cellular and organellar structures, and metabolism are dynamically regulated for neutralizing the pressure of parasitism. However, how modulations of the host cell metabolic pathways support Leishmania infection remains unknown. Herein, we report that lipid accumulation heightens the susceptibility of mice to L. donovani infection and promotes resistance to first-line anti-leishmanial drugs. Despite being pro-inflammatory, the in vitro generated uninfected lipid-laden macrophages (LLMs) or adipose-tissue macrophages (ATMs) display lower levels of reactive oxygen and nitrogen species. Upon infection, LLMs secrete higher IL-10 and lower IL-12p70 cytokines, inhibiting CD4+ T cell activation and Th1 response suggesting a key modulatory role for intramacrophage lipid accumulation in anti-leishmanial host defence. We, therefore, examined this causal relationship between lipids and immunomodulation using an in vivo high-fat diet (HFD) mouse model. HFD increased the susceptibility to L. donovani infection accompanied by a defective CD4+ Th1 and CD8+ T cell response. The white adipose tissue of HFD mice displays increased susceptibility to L. donovani infection with the preferential infection of F4/80+ CD11b+ CD11c+ macrophages with higher levels of neutral lipids reserve. The HFD increased resistance to a first-line anti-leishmanial drug associated with a defective adaptive immune response. These data demonstrate that the accumulation of neutral lipids contributes to susceptibility to visceral leishmaniasis hindering host-protective immune response and reducing the efficacy of antiparasitic drug therapies.

Toll-like receptor 2 selectively modulates Ras isoforms expression in Leishmania major infection.

Leishmania infection of macrophages results in altered Ras isoforms expression and Toll-like receptor-2 (TLR2) expression and functions. Therefore, we examined whether TLR2 would selectively alter Ras isoforms' expression in macrophages. We observed that TLR2 ligands- Pam3CSK4, peptidoglycan (PGN), and FSL- selectively modulated the expression of Ras isoforms in BALB/c-derived elicited macrophages. Lentivirally-expressed TLR1-shRNA significantly reversed this Ras isoforms expression profile. TLR2-deficient L. major-infected macrophages and the lymph node cells from the L. major-infected mice showed similarly reversed Ras isoforms expression. Transfection of the macrophages with the siRNAs for the adaptors- Myeloid Differentiation factor 88 (MyD88) and Toll-Interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP)- or Interleukin-1 Receptor-Associated Kinases (IRAKs)- IRAK1 and IRAK4- significantly inhibited the L. major-induced down-regulation of K-Ras, and up-regulation of N-Ras and H-Ras, expression. The TLR1/TLR2-ligand Pam3CSK4 increased IL-10 and TGF-ß expression in macrophages. Pam3CSK4 upregulated N-Ras and H-Ras, but down-regulated K-Ras, expression in C57BL/6 wild-type, but not in IL-10-deficient, macrophages. IL-10 or TGF-ß signaling inhibition selectively regulated Ras isoforms expression. These observations indicate the specificity of the TLR2 regulation of Ras isoforms and their selective modulation by MyD88, TIRAP, and IRAKs, but not IL-10 or TGF-ß, signaling.

Leishmania donovani Induces Multiple Dynamic Responses in the Metabolome Associated with Amastigote Differentiation and Maturation Inside the Human Macrophage.

Leishmania donovani infection of macrophages drives profound changes in the metabolism of both the host macrophage and the parasite, which undergoes different phases of development culminating in replication and propagation. However, the dynamics of this parasite-macrophage cometabolome are poorly understood. In this study, a multiplatform metabolomics pipeline combining untargeted, high-resolution CE-TOF/MS and LC-QTOF/MS with targeted LC-QqQ/MS was followed to characterize the metabolome alterations induced in L. donovani-infected human monocyte-derived macrophages from different donors at 12, 36, and 72 h post-infection. The set of alterations known to occur during Leishmania infection of macrophages, substantially expanded in this investigation, characterized the dynamics of the glycerophospholipid, sphingolipid, purine, pentose phosphate, glycolytic, TCA, and amino acid metabolism. Our results showed that only citrulline, arginine, and glutamine exhibited constant trends across all studied infection time points, while most metabolite alterations underwent a partial recovery during amastigote maturation. We determined a major metabolite response pointing to an early induction of sphingomyelinase and phospholipase activities and correlated with amino acid depletion. These data represent a comprehensive overview of the metabolome alterations occurring during promastigote-to-amastigote differentiation and maturation of L. donovani inside macrophages that contributes to our understanding of the relationship between L. donovani pathogenesis and metabolic dysregulation.

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling.

While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors. In silico drug screening, supported by subsequent experimental testing, shows that treatment of primary tumors with MAPK pathway inhibitors may further prevent LC migration. In addition, our in silico model predicts treatment combinations that bypass LC dysfunction. In conclusion, our combined approach of in silico and in vivo studies suggests a molecular mechanism that explains how early melanomas develop under the radar of immune surveillance by LC.

Repeatability and Temporal Consistency of Lower Limb Biomechanical Variables Expressing Interlimb Coordination during the Double-Support Phase in People with and without Stroke Sequelae.

Reliable biomechanical methods to assess interlimb coordination during the double-support phase in post-stroke subjects are needed for assessing movement dysfunction and related variability. The data obtained could provide a significant contribution for designing rehabilitation programs and for their monitorisation. The present study aimed to determine the minimum number of gait cycles needed to obtain adequate values of repeatability and temporal consistency of lower limb kinematic, kinetic, and electromyographic parameters during the double support of walking in people with and without stroke sequelae. Eleven post-stroke and thirteen healthy participants performed 20 gait trials at self-selected speed in two separate moments with an interval between 72 h and 7 days. The joint position, the external mechanical work on the centre of mass, and the surface electromyographic activity of the tibialis anterior, soleus, gastrocnemius medialis, rectus femoris, vastus medialis, biceps femoris, and gluteus maximus muscles were extracted for analysis. Both the contralesional and ipsilesional and dominant and non-dominant limbs of participants with and without stroke sequelae, respectively, were evaluated either in trailing or leading positions. The intraclass correlation coefficient was used for assessing intra-session and inter-session consistency analysis. For most of the kinematic and the kinetic variables studied in each session, two to three trials were required for both groups, limbs, and positions. The electromyographic variables presented higher variability, requiring, therefore, a number of trials ranging from 2 to >10. Globally, the number of trials required inter-session ranged from 1 to >10 for kinematic, from 1 to 9 for kinetic, and 1 to >10 for electromyographic variables. Thus, for the double support analysis, three gait trials were required in order to assess the kinematic and kinetic variables in cross-sectional studies, while for longitudinal studies, a higher number of trials (>10) were required for kinematic, kinetic, and electromyographic variables.

Persistent headache attributed to past cervicocephalic artery dissection: clinical characteristics and contributors to headache persistence.

BACKGROUND: Persistent headache/facial/neck pain attributed to past cervicocephalic arterial dissection is under-documented in literature. Our main goal was to evaluate clinical characteristics and contributors to this persistence. METHODS: A retrospective cohort study which included patients with a radiologically confirmed cervicocephalic arterial dissection (2015-2020) in a Portuguese tertiary hospital. Headache persistence was identified through clinical records. A questionnaire aimed to characterize headache in three moments: previous, persistent, and headache at the time of the interview (on average 2.5 years post-event). RESULTS: Ninety-two patients were identified; 24 (26.1%) had headache persistence ≥3 months, and 20 (22.2%) on average after 2.5 years post-event. There were no differences regarding demographics and vascular risk factors among patients with (n = 22) and without (n = 68) headache persistence. The first group had higher previous headache history (68.2% vs 4.4%, p < 0.001), delay in diagnosis (3.6 vs 1.9 days, p < 0.001), and headache/cervicalgia as the first symptom (81.8% vs 41.2%, p < 0.001). At the time of the interview, 20% still reported daily headache. A logistic regression model depicted headache history (OR = 59.8, p < 0.001), acute headache/cervicalgia (odds ratio, OR = 25.4, p = 0.005), posterior circulation dissection (OR = 7.6, p < 0.001), and less than 4 points by National Institutes of Health Stroke Scale score (OR = 5.0, p = 0.025) as contributors to headache persistence. CONCLUSION: Headache persistence post-cervicocephalic arterial dissection is common, and frequently affects patients daily. As it potentially affects functional outcomes and quality of life, the contributors identified in this study may help clinicians manage patients after the acute event.

Postural control during turn on the light task assisted by functional electrical stimulation in post stroke subjects.

Postural control mechanisms have a determinant role in reaching tasks and are typically impaired in post-stroke patients. Functional electrical stimulation (FES) has been demonstrated to be a promising therapy for improving upper limb (UL) function. However, according to our knowledge, no study has evaluated FES influence on postural control. This study aims to evaluate the influence of FES UL assistance, during turning on the light task, in the related postural control mechanisms. An observational study involving ten post-stroke subjects with UL dysfunction was performed. Early and anticipatory postural adjustments (EPAs and APAs, respectively), the weight shift, the center of pressure and the center of mass (CoM) displacement were analyzed during the turning on the light task with and without the FES assistance. FES parameters were adjusted to improve UL function according to a consensus between physiotherapists' and patients' perspectives. The ANOVA repeated measures, Paired sample t and McNemar tests were used to compare postural control between the assisted and non-assisted conditions. When the task was assisted by FES, the number of participants that presented APAs increased (p = 0.031). UL FES assistance during turning on the light task can improve postural control in neurological patients with UL impairments.

Usability of Functional Electrical Stimulation in Upper Limb Rehabilitation in Post-Stroke Patients: A Narrative Review.

Stroke leads to significant impairment in upper limb (UL) function. The goal of rehabilitation is the reestablishment of pre-stroke motor stroke skills by stimulating neuroplasticity. Among several rehabilitation approaches, functional electrical stimulation (FES) is highlighted in stroke rehabilitation guidelines as a supplementary therapy alongside the standard care modalities. The aim of this study is to present a comprehensive review regarding the usability of FES in post-stroke UL rehabilitation. Specifically, the factors related to UL rehabilitation that should be considered in FES usability, as well a critical review of the outcomes used to assess FES usability, are presented. This review reinforces the FES as a promising tool to induce neuroplastic modifications in post-stroke rehabilitation by enabling the possibility of delivering intensive periods of treatment with comparatively less demand on human resources. However, the lack of studies evaluating FES usability through motor control outcomes, specifically movement quality indicators, combined with user satisfaction limits the definition of FES optimal therapeutical window for different UL functional tasks. FES systems capable of integrating postural control muscles involving other anatomic regions, such as the trunk, during reaching tasks are required to improve UL function in post-stroke patients.

Optimal multi-field functional electrical stimulation parameters for the "drinking task - reaching phase" and related upper limb kinematics repeatability in post stroke subjects.

BACKGROUND: No specific guidelines for the management of functional electrical stimulation (FES) parameters in post stroke patients have been defined yet, despite its frequent use. The purpose of this study is to characterize the optimal FES parameters that assist the reaching phase of drinking task ("drinking task - reaching phase") on post stroke subjects and to analyze the related upper limb (UL) movement quality indicators repeatability. METHODS: An observational study with a test and re-test design involving ten post stroke subjects with UL dysfunction was performed. End-point and joint kinematics of contralesional UL were assessed during the "drinking task - reaching phase" with FES through a test and retest design. FES parameters were adjusted to improve UL function according to a consensus between physiotherapists and patients' perspective. FINDINGS: It was possible to establish reliable FES parameters that assisted the "drinking task - reaching phase". All FES parameters presented high to very high repeatability and led to moderate to very high repeatability in almost UL movement quality indicators during the "drinking task - reaching phase". INTERPRETATION: These findings show that the main characteristics of FES parameters that improves patient perception of change are quite stable, which facilitate its implementation in clinical practice by allowing consistence between intervention sessions.

Update about the disrupting-effects of phthalates on the human reproductive system.

Phthalate esters are synthetic chemicals used in the plastic industry as plasticizers and consumable products. According to United Nations, about 400 million tons of plastic are produced every year. In parallel with increased production, the concerns about its effects on human health have increased because phthalates are endocrine-disrupting compounds. Humans are continuously exposed to phthalates through different routes of exposure. Experimental data have associated the phthalates exposure to adverse effects on development and reproduction in women (e.g., earlier puberty, primary ovarian insufficiency, endometriosis, preterm birth, or in vitro fertilization) and men (e.g., anogenital distance, cryptorchidism, hypospadias, and changes in adult reproductive function) although there is no consensus. Therefore, one question arises: could the increase in infertility be related to phthalates exposure? To answer this question, we aimed to assess the disrupting-effects of phthalates on the human reproductive system. For this, we reviewed the current literature based on epidemiological and experimental data and experimental studies in humans. The phthalate effects were discussed in a separate mode for female and male reproductive systems. In summary, phthalates induce toxicity in the reproductive system and human development. The increased plastic production may be related to the increase in human infertility.

Obesity effects on muscular activity during lifting and lowering tasks.

Obesity is an emerging health problem and its incidence has been increasing throughout the workforce. In industrial workstations, vertical handling tasks (VHT), including lifting and lowering, are very common and can cause a significant muscular overload for the involved workers. During these tasks, muscular activity may be considerably affected by workers' body conditions. This study aims to analyze and compare the muscular activity in subjects with different obesity levels, using surface electromyography (EMG), during predefined VHT. Six different VHT (combining 5, 10 and 15-kg loads with two task styles) were performed. EMG data normalization was based on the percentage of maximum contraction during each task (MCT%). The results show that obesity influences the MCT%, which in turn increases the muscular effort during VHT. The current investigation demonstrates that obesity is a relevant musculoskeletal risk factor regarding VHT. The engineering analysis and design implications of this work can thus be perceived.

Cytokines and metabolic regulation: A framework of bidirectional influences affecting Leishmania infection.

Leishmania, a protozoan parasite inflicting the complex of diseases called Leishmaniases, resides and replicates as amastigotes within mammalian macrophages. As macrophages are metabolically highly active and can generate free radicals that can destroy this parasite, Leishmania also devise strategies to modulate the host cell metabolism. However, the metabolic changes can also be influenced by the anti-leishmanial immune response mediated by cytokines. This bidirectional, dynamic and complex metabolic coupling established between Leishmania and its host is the result of a long co-evolutionary process. Due to the continuous alterations imposed by the host microenvironment, such metabolic coupling continues to be dynamically regulated. The constant pursuit and competition for nutrients in the host-Leishmania duet alter the host metabolic pathways with major consequences for its nutritional reserves, eventually affecting the phenotype and functionality of the host cell. Altered phenotype and functions of macrophages are particularly relevant to immune cells, as perturbed metabolic fluxes can crucially affect the activation, differentiation, and functions of host immune cells. All these changes can deterministically direct the outcome of an infection. Cytokines and metabolic fluxes can bidirectionally influence each other through molecular sensors and regulators to dictate the final infection outcome. Our studies along with those from others have now identified the metabolic nodes that can be targeted for therapy.

Optimal Multifield Functional Electrical Stimulation Parameters for the "Turn on the Light" Task and Related Upper Limb Kinematics Repeatability in Poststroke Subjects.

OBJECTIVE: To characterize the optimal functional electrical stimulation (FES) parameters that assist the turn on the light task (TOTL) on poststroke participants and to analyze the related upper limb (UL) kinematics repeatability. DESIGN: Cross-sectional study. SETTING: Human movement research center. PARTICIPANTS: Poststroke individuals (N=11) with history of a single unilateral stroke that resulted in a motor control dysfunction of the contralesional UL. INTERVENTIONS: FES based on surface multifield technology applied to the contralesional wrist and finger extensors during the TOTL. MAIN OUTCOME MEASURES: FES outcome metrics (virtual electrodes, stimulation duration, intensity) and kinematic metrics (end-point kinematics [absolute and relative duration, mean and peak velocities, relative instant of peak velocity, index of curvature, number of movement units] and joint kinematics [shoulder, elbow, wrist end position and range of movement]). Outcome measures were assessed 2 times with a 72-hour maximum time interval. CONCLUSION: It was possible to establish reliable FES parameters that assisted the TOTL on poststroke participants. These stimulation parameters led to high to very high repeatability in terms of UL kinematics for most of the cases.

Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity.

In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus. Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy.

Comparison of upper limb kinematics in two activities of daily living with different handling requirements.

INTRODUCTION: Recently, kinematic analysis of the drinking task (DRINK) has been recommended to assess the quality of upper limb (UL) movement after stroke, but the accomplishment of this task may become difficult for poststroke patients with hand impairment. Therefore, it is necessary to study ADLs that involve a simpler interaction with a daily life target, such as the turning on a light task (LIGHT). As the knowledge of movement performed by healthy adults becomes essential to assess the quality of movement of poststroke patients, the main goal of this article was to compare the kinematic strategies used by healthy adults in LIGHT with those that are used in DRINK. METHODS: 63 adults, aged 30 to 69 years old, drank water and turned on a light, using both ULs separately, while seated. The movements of both tasks were captured by a 3D motion capture system. End-point and joint kinematics of reaching and returning phases were analysed. A multifactorial analysis of variance with repeated measures was applied to the kinematic metrics, using age, sex, body mass index and dominance as main factors. RESULTS: Mean and peak velocities, index of curvature, shoulder flexion and elbow extension were lower in LIGHT, which suggests that the real hand trajectory was smaller in this task. In LIGHT, reaching was less smooth and returning was smoother than DRINK. The instant of peak velocity was similar in both tasks. There was a minimal anterior trunk displacement in LIGHT, and a greater anterior trunk displacement in DRINK. Age and sex were the main factors which exerted effect on some of the kinematics, especially in LIGHT. CONCLUSION: The different target formats and hand contact in DRINK and LIGHT seem to be responsible for differences in velocity profile, efficiency, smoothness, joint angles and trunk displacement. Results suggest that the real hand trajectory was smaller in LIGHT and that interaction with the switch seems to be less demanding than with the glass. Accordingly, LIGHT could be a good option for the assessment of poststroke patients without grasping ability. Age and sex seem to be the main factors to be considered in future studies for a better match between healthy and poststroke adults.

IL-17A and IL-17F orchestrate macrophages to promote lung cancer.

PURPOSE: Previously, inflammation has been found to be associated with the development of lung cancer. Despite their well-characterized pro-inflammatory functions, the putative roles of interleukin-17 (IL-17) cytokine family members in tumorigenesis have remained controversial. While IL-17A exhibits both pro- and anti-tumor effects, IL-17F has been suggested to serve as a candidate for cancer therapy. Thus, we aimed at clarifying the involvement of IL-17A/F in lung cancer. METHODS: IL-17 receptor expression in human and murine lung cancer cells was assessed using immunofluorescence. The effect of IL-17A/F stimulation on lung cancer cell viability (SRB assay) and metabolism (glucose consumption and lactate production) was evaluated under normoxic and hypoxic conditions. Characterization of IL-17A/F-stimulated macrophages was performed by flow cytometry and ELISA. The effect of conditioned media (CM) from IL-17A/F-stimulated macrophages was evaluated on lung cancer cell migration. The effect of CM-stimulated macrophages on lung tumor growth, proliferation and angiogenesis was evaluated in vivo using a chicken chorioallantoic membrane (CAM) assay. RESULTS: No alterations in lung cancer cell viability or metabolism were observed upon direct stimulation with IL-17A/F. We found, however, that CM from IL-17A/F-stimulated macrophages promoted both murine and human lung cancer cell progression through an increased migration capacity in vitro and enhanced in vivo tumor growth, proliferation and angiogenesis. These findings were supported by an increased polarization of human macrophages towards a M2-like phenotype. CONCLUSIONS: Our data indicate that IL-17A/F act through immune cell orchestration, i.e., of macrophages, to promote lung cancer cell growth and progression. In addition, our data provide a link between IL-17A/F activity and lung cancer cell-macrophage crosstalk.

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis.

BACKGROUND: The disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown. METHODS: We performed transcriptomics in uninfected and L. donovani-infected macrophages 6 hours post-infection. Glutamine quantification by HPLC was assessed in the supernatant of macrophages throughout the infection course. For experimental L. donovani infections, mice were infected with 1.0 x 108 stationary L. donovani promastigotes. Glutaminase (GLS) chemical inhibition was performed using BPTES and glutamine was administered throughout infection. For combined therapy experiment, a daily administration of miltefosine and glutamine was performed by oral gavage. Parasite burden was determined using a Taqman-based assay. Immune cell phenotyping and cytotoxicity were performed in splenic cells using flow cytometry. FINDINGS: We show that glutamine is essential for the control of L. donovani infection. Transcriptomic analysis of L. donovani-infected macrophages demonstrated an upregulation of genes involved in glutamine metabolism. Pharmacological inhibition of glutaminolysis significantly increased the susceptibility to infection, accompanied by an increased recruitment of anti-inflammatory myeloid cells and impaired T cell responses. Remarkably, the supplementation of glutamine to mice infected with L. donovani during miltefosine treatment potentiates parasite clearance through the development of a more effective anti-Leishmania adaptive immune response. CONCLUSIONS: Our data indicates that dietary glutamine supplementation may act as a promising adjuvant for the treatment of visceral leishmaniasis.

The Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis.

Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α-/- macrophages. L. donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells.