Single-Cell Transcriptomic Analysis Links Nonmyelinating Schwann Cells to Proinflammatory Response in the Lung.

The lung is a barrier tissue with constant exposure to the inhaled environment. Therefore, innate immunity against particulates and pathogens is of critical importance to maintain tissue homeostasis. Although the lung harbors both myelinating and nonmyelinating Schwann cells (NMSCs), NMSCs represent the most abundant Schwann cell (SC) population in the lung. However, their contribution to lung physiology remains largely unknown. In this study, we used the human glial fibrillary acidic protein promoter driving tdTomato expression in mice to identify SCs in the peripheral nervous system and determine their location within the lung. Single-cell transcriptomic analysis revealed the existence of two NMSC populations (NMSC1 and NMSC2) that may participate in pathogen recognition. We demonstrated that these pulmonary SCs produce chemokines and cytokines upon LPS stimulation using in vitro conditions. Furthermore, we challenged mouse lungs with LPS and found that NMSC1 exhibits an enriched proinflammatory response among all SC subtypes. Collectively, these findings define the molecular profiles of lung SCs and suggest a potential role for NMSCs in lung inflammation.

IL-23 signaling is not an important driver of liver inflammation and fibrosis in murine non-alcoholic steatohepatitis models.

Non-alcoholic fatty liver disease (NAFLD), represents an unmet medical need that can progress to non-alcoholic steatohepatitis (NASH), which, without intervention, can result in the development of cirrhosis and hepatocellular carcinoma (HCC). Inflammation is a pathological hallmark of NASH, and targeting key inflammatory mediators of NASH may lead to potential therapeutics for the disease. Herein, we aimed to investigate the role of IL-23 signaling in NASH progression in murine models. We showed that recombinant IL-23 can promote IL-17 producing cell expansion in the liver and that these cells are predominately γδ T cells and Mucosal Associated Invariant T cells (MAITs). Reciprocally, we found that IL-23 signaling is necessary for the expansion of γδ T cells and MAIT cells in the western diet (WD) diet induced NASH model. However, we did not observe any significant differences in liver inflammation and fibrosis between wild type and Il23r-/- mice in the same NASH model. Furthermore, we found that Il23r deletion does not impact liver inflammation and fibrosis in the choline-deficient, L-amino acid-defined and high-fat diet (CDA-HFD) induced NASH model. Based on these findings, we therefore propose that IL-23 signaling is not necessary for NASH pathogenesis in preclinical models and targeting this pathway alone may not be an effective therapeutic approach to ameliorate the disease progression in NASH patients.

A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment.

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.

Enfermedad cardiovascular en pacientes con insuficiencia renal crónica estadios IV y V

Introducción. La primera causa de muerte en pacientes con insuficiencia renal crónica (IRC) estadios IV y V es la enfermedad cardiovascular (ECV). Objetivo. Identificar ECV en pacientes con IRC estadios IV y V. Método. Se realizó un estudio transversal de Abril de 2013 a Abril de 2014, en el Servicio Nefrológico del Hospital Lucía Íñiguez Landín, Holguín, Cuba. Se seleccionaron 84 pacientes por muestreo sistemático: 48 con IRC estadio IV y 36 en hemodiálisis. Se realizó a cada paciente: examen clínico, electrocardiograma y ecocardiograma 2D con Doppler. Se determinaron: edad, función ventricular, tipo y cantidad (Nº) de ECV. Se utilizó test de Chi cuadrado para asociación de variables. Resultados. Predominaron en los pacientes con IRC estadio IV las edades de 41-50 años (33,3%) y más de 60 años (33,3%), con IRC estadio V el grupo etario de 41-50 años (44,4%; p=0,30). El 91% de los pacientes con IRC estadio IV y el 100% de los estadio V (p=0,20) tenían disfunción diastólica (DD). En los pacientes con IRC estadio IV, la miocardiopatía hipertrófica (MCPH) se identificó en el 50%, la cardiopatía isquémica (CI) en el 25% y la miocardiopatía urémica (MCPU), también, en el 25%; con IRC estadio V, la MCPH fue del 88% (p=0,008), la CI del 66% (p=0,007), las valvulopatías del 55% (p=0,000) y la pericarditis del 33% (p=0,20). El 41% de los pacientes con IRC estadio IV tenían dos lesiones cardíacas y el 77,7% de los pacientes con IRC estadio V tenían más de tres lesiones (p=0,01). Conclusiones. Todos los pacientes con IRC estadio V tenían ECV con DD, la mayoría con más de tres afecciones diferentes; las más frecuentes fueron MCPH, CI y valvulopatías. Mientras que MCPH, CI y MCPU fueron las principales ECV en pacientes con IRC estadio IV.

Cardiovascular disease in patients with stage IV and V of chronic kidney disease Introduction. The cardiovascular disease (CVD) is the first cause of death in patients with stage IV and V of chronic kidney disease (CKD). Objective. To identify the CVD in patients with stage IV and V of CKD. Method. Through a systematic selection, 84 patients (48 stage IV CKD and 36 stage V CKD) were include in a cross-sectional study from April 2013 to April 2014 in the Nephrological Centre of Lucía Íñiguez Hospital, Holguín, Cuba. Clinical examination, electrocardiogram, 2D and Doppler echocardiogram were made to them. Age, ventricular function, type of CVD and number of CVD associated were study. Chi-square test was used as statistical analysis. Results. The ages of 41-50 years (33%) and over 60 years (33%) predominated in patients with stage IV CKD and the ages of 41-50 years (44.4%, p=0.30) in stage V CKD. The 91% of patients with stage IV CKD and the 100% with stage V CKD (p=0.20) had diastolic dysfunction (DD). In patients with stage IV CKD, hypertrophic cardiomyopathy (HMCP) was identified in 50%, coronary artery disease (CAD) in 25% and uremic cardiomyopathy (UMCP) also in 25%; in patients with stage V CKD, the HMCP was 88% (p=0.008), CAD 66% (p=0.007), valvular heart disease (VHD) 55% (p=0.000) and pericarditis 33% (p=0.20). The 41% of patients with stage IV CKD had two ECV and 77.7% of patients with stage V CKD had more than three ECV (p=0.01). Conclusion. All patients with stage V CKD had CVD with DD, most with more than three CVD; HCMP, CAD and VHD were the principal CVD; while HCMP, CAD and UCMP were the principal CVD in patients with stage IV CKD.

Doença cardiovascular em pacientes com doença renal crônica estágio IV e V Introdução. A principal causa de morte em pacientes com renal crônica (DRC) estágio IV e V é a doença cardiovascular (DCV). Objetivo. Identificar DCV em pacientes com DRC estágios IV e V. Método. Um estudo transversal foi realizado de Abril de 2013 a Abril de 2014, no Serviço de Nefrologia do Hospital Lucía Íñiguez Landín, Holguín, Cuba. Foram selecionados por amostragem sistemática 84 pacientes: 48 com DRC estágio IV e 36 com DRC em hemodiálise. Foram submetidos a exame clínico, eletrocardiograma e ecocardiografia 2D e Doppler. Foram determinados: idade, função ventricular, tipo e número (nº) de DCV. Foi utilizado o teste do Qui-quadrado para associação das variáveis. Resultados. Predominou em pacientes com DRC estágio IV as idades de 41-50 anos (33,3%) e >60 anos (33,3%), com DRC estágio V a faixa etária 41-50 anos (44,4%; p=0,30). O 91% dos pacientes com DRC estágio IV e 100% com DRC estágio V (p=0,20) apresentaram disfunção diastólica (DD). Em pacientes com DRC estágio IV, a cardiomiopatia hipertrófica (CMPH) foi identificado em 50%, a doença arterial coronariana (DAC) em 25% e cardiomiopatia urêmica (CMPU) também em 25%; com DRC estágio V, o CMPH foi de 88% (p=0,008), DAC de 66% (p=0,007), doença cardíaca valvular de 55% (p=0,000) e pericardite 33% (p=0,20). O 41% dos pacientes com DRC estágio IV teve duas DCV e 77,7% dos pacientes com DRC estágio V teve mais de três DCV (p = 0,01). Conclusões. Todos os pacientes com DRC estágio V teve CVD com DD, a maioria com mais de três DCV; as mais frequentes foram CMPH, DAC e doença cardíaca valvular. Enquanto CMPH, DAC e CMPU foram o principal DCV em pacientes com DRC estágio IV.

Enfermedad cardiovascular en pacientes con insuficiencia renal crónica estadios IV y V

Introducción. La primera causa de muerte en pacientes con insuficiencia renal crónica (IRC) estadios IV y V es la enfermedad cardiovascular (ECV). Objetivo. Identificar ECV en pacientes con IRC estadios IV y V. Método. Se realizó un estudio transversal de Abril de 2013 a Abril de 2014, en el Servicio Nefrológico del Hospital Lucía Iñiguez Landín, Holguín, Cuba. Se seleccionaron 84 pacientes por muestreo sistemático: 48 con IRC estadio IV y 36 en hemodiálisis. Se realizó a cada paciente: examen clínico, electrocardiograma y ecocardiograma 2D con Doppler. Se determinaron: edad, función ventricular, tipo y cantidad (Nº) de ECV. Se utilizó test de Chi cuadrado para asociación de variables. Resultados. Predominaron en los pacientes con IRC estadio IV las edades de 41-50 años (33,3%) y más de 60 años (33,3%), con IRC estadio V el grupo etario de 41-50 años (44,4%; p=0,30). El 91% de los pacientes con IRC estadio IV y el 100% de los estadio V (p=0,20) tenían disfunción diastólica (DD). En los pacientes con IRC estadio IV, la miocardiopatía hipertrófica (MCPH) se identificó en el 50%, la cardiopatía isquémica (CI) en el 25% y la miocardiopatía urémica (MCPU), también, en el 25%; con IRC estadio V, la MCPH fue del 88% (p=0,008), la CI del 66% (p=0,007), las valvulopatías del 55% (p=0,000) y la pericarditis del 33% (p=0,20). El 41% de los pacientes con IRC estadio IV tenían dos lesiones cardíacas y el 77,7% de los pacientes con IRC estadio V tenían más de tres lesiones (p=0,01). Conclusiones. Todos los pacientes con IRC estadio V tenían ECV con DD, la mayoría con más de tres afecciones diferentes; las más frecuentes fueron MCPH, CI y valvulopatías. Mientras que MCPH, CI y MCPU fueron las principales ECV en pacientes con IRC estadio IV.(AU)

Cardiovascular disease in patients with stage IV and V of chronic kidney disease Introduction. The cardiovascular disease (CVD) is the first cause of death in patients with stage IV and V of chronic kidney disease (CKD). Objective. To identify the CVD in patients with stage IV and V of CKD. Method. Through a systematic selection, 84 patients (48 stage IV CKD and 36 stage V CKD) were include in a cross-sectional study from April 2013 to April 2014 in the Nephrological Centre of Lucía Iñiguez Hospital, Holguín, Cuba. Clinical examination, electrocardiogram, 2D and Doppler echocardiogram were made to them. Age, ventricular function, type of CVD and number of CVD associated were study. Chi-square test was used as statistical analysis. Results. The ages of 41-50 years (33%) and over 60 years (33%) predominated in patients with stage IV CKD and the ages of 41-50 years (44.4%, p=0.30) in stage V CKD. The 91% of patients with stage IV CKD and the 100% with stage V CKD (p=0.20) had diastolic dysfunction (DD). In patients with stage IV CKD, hypertrophic cardiomyopathy (HMCP) was identified in 50%, coronary artery disease (CAD) in 25% and uremic cardiomyopathy (UMCP) also in 25%; in patients with stage V CKD, the HMCP was 88% (p=0.008), CAD 66% (p=0.007), valvular heart disease (VHD) 55% (p=0.000) and pericarditis 33% (p=0.20). The 41% of patients with stage IV CKD had two ECV and 77.7% of patients with stage V CKD had more than three ECV (p=0.01). Conclusion. All patients with stage V CKD had CVD with DD, most with more than three CVD; HCMP, CAD and VHD were the principal CVD; while HCMP, CAD and UCMP were the principal CVD in patients with stage IV CKD.(AU)

Doenþa cardiovascular em pacientes com doenþa renal cr¶nica estágio IV e V IntroduþÒo. A principal causa de morte em pacientes com renal cr¶nica (DRC) estágio IV e V é a doenþa cardiovascular (DCV). Objetivo. Identificar DCV em pacientes com DRC estágios IV e V. Método. Um estudo transversal foi realizado de Abril de 2013 a Abril de 2014, no Serviþo de Nefrologia do Hospital Lucía Iñiguez Landín, Holguín, Cuba. Foram selecionados por amostragem sistemática 84 pacientes: 48 com DRC estágio IV e 36 com DRC em hemodiálise. Foram submetidos a exame clínico, eletrocardiograma e ecocardiografia 2D e Doppler. Foram determinados: idade, funþÒo ventricular, tipo e número (nº) de DCV. Foi utilizado o teste do Qui-quadrado para associaþÒo das variáveis. Resultados. Predominou em pacientes com DRC estágio IV as idades de 41-50 anos (33,3%) e >60 anos (33,3%), com DRC estágio V a faixa etária 41-50 anos (44,4%; p=0,30). O 91% dos pacientes com DRC estágio IV e 100% com DRC estágio V (p=0,20) apresentaram disfunþÒo diastólica (DD). Em pacientes com DRC estágio IV, a cardiomiopatia hipertrófica (CMPH) foi identificado em 50%, a doenþa arterial coronariana (DAC) em 25% e cardiomiopatia urÛmica (CMPU) também em 25%; com DRC estágio V, o CMPH foi de 88% (p=0,008), DAC de 66% (p=0,007), doenþa cardíaca valvular de 55% (p=0,000) e pericardite 33% (p=0,20). O 41% dos pacientes com DRC estágio IV teve duas DCV e 77,7% dos pacientes com DRC estágio V teve mais de trÛs DCV (p = 0,01). Conclus§es. Todos os pacientes com DRC estágio V teve CVD com DD, a maioria com mais de trÛs DCV; as mais frequentes foram CMPH, DAC e doenþa cardíaca valvular. Enquanto CMPH, DAC e CMPU foram o principal DCV em pacientes com DRC estágio IV.(AU)

Eosinophils secrete IL-4 to facilitate liver regeneration.

The liver is a central organ for the synthesis and storage of nutrients, production of serum proteins and hormones, and breakdown of toxins and metabolites. Because the liver is susceptible to toxin- or pathogen-mediated injury, it maintains a remarkable capacity to regenerate by compensatory growth. Specifically, in response to injury, quiescent hepatocytes enter the cell cycle and undergo DNA replication to promote liver regrowth. Despite the elucidation of a number of regenerative factors, the mechanisms by which liver injury triggers hepatocyte proliferation are incompletely understood. We demonstrate here that eosinophils stimulate liver regeneration after partial hepatectomy and toxin-mediated injury. Liver injury results in rapid recruitment of eosinophils, which secrete IL-4 to promote the proliferation of quiescent hepatocytes. Surprisingly, signaling via the IL-4Rα in macrophages, which have been implicated in tissue repair, is dispensable for hepatocyte proliferation and liver regrowth after injury. Instead, IL-4 exerts its proliferative actions via IL-4Rα in hepatocytes. Our findings thus provide a unique mechanism by which eosinophil-derived IL-4 stimulates hepatocyte proliferation in regenerating liver.

Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration.

In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues.

IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity.

Immune cells take residence in metabolic tissues, providing a framework for direct regulation of nutrient metabolism. Despite conservation of this anatomic relationship through evolution, the signals and mechanisms by which the immune system regulates nutrient homeostasis and insulin action remain poorly understood. Here, we demonstrate that the IL-4/STAT6 immune axis, a key pathway in helminth immunity and allergies, controls peripheral nutrient metabolism and insulin sensitivity. Disruption of signal transducer and activator of transcription 6 (STAT6) decreases insulin action and enhances a peroxisome proliferator-activated receptor α (PPARα) driven program of oxidative metabolism. Conversely, activation of STAT6 by IL-4 improves insulin action by inhibiting the PPARα-regulated program of nutrient catabolism and attenuating adipose tissue inflammation. These findings have thus identified an unexpected molecular link between the immune system and macronutrient metabolism, suggesting perhaps the coevolution of these pathways occurred to ensure access to glucose during times of helminth infection.

PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance.

Macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses against self antigens. Although factors participating in recognition and engulfment of apoptotic cells have been identified, the transcriptional basis for the sensing and the silent disposal of apoptotic cells is unknown. Here we show that peroxisome proliferator-activated receptor-delta (PPAR-delta) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR-delta decreases expression of opsonins such as complement component-1qb (C1qb), resulting in impairment of apoptotic cell clearance and reduction in anti-inflammatory cytokine production. This increases autoantibody production and predisposes global and macrophage-specific Ppard(-/-) mice to autoimmune kidney disease, a phenotype resembling the human disease systemic lupus erythematosus. Thus, PPAR-delta has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained.

TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism.

During fasting, increased concentrations of circulating catecholamines promote the mobilization of lipid stores from adipose tissue in part by phosphorylating and inactivating acetyl-coenzyme A carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis. Here, we describe a parallel pathway, in which the pseudokinase Tribbles 3 (TRB3), whose abundance is increased during fasting, stimulates lipolysis by triggering the degradation of ACC in adipose tissue. TRB3 promoted ACC ubiquitination through an association with the E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1). Indeed, adipocytes deficient in TRB3 accumulated larger amounts of ACC protein than did wild-type cells. Because transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation, these results demonstrate how phosphorylation and ubiquitination pathways converge on a key regulator of lipid metabolism to maintain energy homeostasis.