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Macrophages are a heterogeneous population of innate immune cells that support tissue homeostasis through their involvement in tissue development and repair, and pathogen defense. Emerging data reveal that metabolism may control macrophage polarization and function and, conversely, phenotypic polarization may drive metabolic reprogramming. Here, using biochemical analysis, correlative cryogenic fluorescence microscopy and cryo-focused ion-beam scanning electron microscopy, we demonstrate that growth hormone (GH) functions as a metabolic modulator to reprogram inflammatory GM-CSF-primed monocyte-derived macrophages (GM-MØ). We found that exogenous treatment of GM-MØ with recombinant human GH suppressed glycolysis, lactate production and non-mitochondrial respiration, and enhanced mitochondrial oxidative phosphorylation. Likewise, GH treatment augmented mitochondrial volume and altered mitochondrial dynamics, including the remodeling of the inner membrane to increase the density of cristae. Our data demonstrate that GH likely serves a modulatory role in the metabolism of inflammatory macrophages and suggest that metabolic reprogramming of macrophages should be considered a new target to intervene in multiple inflammatory diseases.

SignificanceNew imaging-based approaches are incorporating new concepts to our knowledge of biological processes. The analysis of receptor dynamics involved in cell movement using single-particle tracking demonstrates that cells require chemokine-mediated receptor clustering to sense appropriately chemoattractant gradients. Here, we report that this process does not occur in T cells expressing CXCR4R334X, a mutant form of CXCR4 linked to WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis). The underlaying molecular mechanism involves inappropriate actin cytoskeleton remodeling due to the inadequate β-arrestin1 activation by CXCR4R334X, which alters its lateral mobility and spatial organization. These defects, associated to CXCR4R334X expression, contribute to the retention of hematopoietic precursors in bone marrow niches and explain the severe immunological symptoms associated with WHIM syndrome., Proceedings of the National Academy of Sciences of the United States of America, 119 (21), ISSN:0027-8424, ISSN:1091-6490

The most representative indicator of vitamin D status in clinical practice is 25(OH)D3, but new biomarkers could improve the assessment of vitamin D status and metabolism. The objective of this study is to investigate the association of serum vitamin D metabolites and vitamin D metabolite ratios (VMRs) with potentially influential factors in premenopausal women. This is a cross-sectional study based on 1422 women, aged 39-50, recruited from a Madrid Medical Diagnostic Center. Participants answered an epidemiological and a food frequency questionnaire. Serum vitamin D metabolites were determined using an SPE-LC-MS/MS platform. The association between participant's characteristics, vitamin D metabolites, and VMRs was quantified by multiple linear regression models. Mean 25(OH)D3 concentration was 49.2 + 18.9 nmol/L, with greater deficits among obese, nulliparous, dark-skinned women, and with less sun exposure. A lower R2 ratio (1,25(OH)2D3/25(OH)D3) and a higher R4 (24,25(OH)2D3/1,25(OH)2D3) were observed in nulliparous women, with high sun exposure, and those with low caloric intake or high consumption of calcium, vitamin D supplements, or alcohol. Nulliparous women had lower R1 (25(OH)D3/Vit D3) and R3 (24,25(OH)2D3/25(OH)D3), and older women showed lower R3 and R4. Vitamin D status modified the association of the VMRs with seasons. VMRs can be complementary indicators of vitamin D status and its endogenous metabolism, and reveal the influence of certain individual characteristics on the expression of hydroxylase enzymes. This study was funded by the Spanish Ministry of Health (EC11–273) and by the Carlos III Institute of Health (PI15CIII/0029). The article presents independent research. The views expressed are those of the authors and not necessarily those of the Carlos III Institute of Health. Sí

The role of vitamin D in mammographic density is still unclear. This study examines the association between serum 25-hydroxyvitamin D (25(OH)D) and mammographic density, overall and by specific women characteristics. DDM-Madrid is a cross-sectional study that recruited 1403 premenopausal women in a breast radiodiagnosis unit of Madrid City Council. Information was collected with a questionnaire and plasma 25(OH)D was measured by solid-phase extraction on-line coupled to liquid chromatography–tandem mass spectrometry. Percent mammographic density was assessed using a semi-automated computer tool (DM-Scan). Multivariable linear regression models were used to quantify the associations, categorizing 25(OH)D levels (nmol/L) into 3 groups according to the cut-offs established by the US Endocrine Society. Models were adjusted for age, education, body mass index, age at menarche, parity, previous breast biopsies, family history of breast cancer, physical activity, energy intake, use of corticoids, hypercholesterolemia and day of sample extraction. Mean serum 25(OH)D level was 49.4 + 18.9 nmol/L. Women with sufficient concentrations of 25(OH)D showed a slight decrease in mammographic density (β >75nmol/L=-3.40; p = 0.037). No differences were observed according to women characteristics except for parity, where the protective effect of 25(OH)D was only seen among nulliparous (β >75nmol/L=-13.00; p-heterogeneity = 0.006). In light of the protective effect of vitamin D on mammographic density and the high prevalence of vitamin D insufficiency in our population, improving these levels could be an effective measure for the prevention of health problems related to the lack of this essential vitamin.

[EN] Introduction: Mammographic density (MD), the proportion of radiologically dense breast tissue, is a strong risk factor for breast cancer. Our objective is to investigate the influence of occupations and occupational exposure to physical, chemical, and microbiological agents on MD in Spanish premenopausal women. Methods: This is a cross-sectional study based on 1362 premenopausal workers, aged 39-50, who attended a gynecological screening in a breast radiodiagnosis unit of Madrid City Council. The work history was compiled through a personal interview. Exposure to occupational agents was evaluated using the Spanish job-exposure matrix MatEmESp. MD percentage was assessed using the validated semi-automated computer tool DM-Scan. The association between occupation, occupational exposures, and MD was quantified using multiple linear regression models, adjusted for age, educational level, body mass index, parity, previous breast biopsies, family history of breast cancer, energy intake, use of oral contraceptives, smoking, and alcohol consumption. Results: Although no occupation was statistically significantly associated with MD, a borderline significant inverse association was mainly observed in orchard, greenhouse, nursery, and garden workers (beta = -6.60; 95% confidence interval (95%CI) = -14.27; 1.07) and information and communication technology technicians (beta = -7.27; 95%CI = -15.37; 0.84). On the contrary, a positive association was found among technicians in art galleries, museums, and libraries (beta = 8.47; 95%CI = -0.65; 17.60). Women occupationally exposed to fungicides, herbicides, and insecticides tended to have lower MD. The percentage of density decreased by almost 2% for every 5 years spent in occupations exposed to the mentioned agents. Conclusions: Although our findings point to a lack of association with the occupations and exposures analyzed, this study supports a deeper exploration of the role of certain occupational agents in MD, such as pesticides., This work was supported by the Carlos III Institute of Health (AESI PI15CIII/00029 and AESI PI15CIII/00013). The article presents independent research. The views expressed are those of the authors and not necessarily those of the Carlos III Institute of Health.

This study investigates the still uncertain association between serum phospholipid fatty acids (PL-FA), and anthropometric and adiposity variables. A cross-sectional study was conducted with 1443 Spanish premenopausal women. Participants answered an epidemiological and a food frequency questionnaire. Anthropometric variables were measured using a bioimpedance scale. Serum PL-FAs levels were determined by gas chromatography&ndash, mass spectrometry. The association between body mass index (BMI), weight gain, body fat percentage, visceral fat index, and waist circumference with serum PL-FAs and desaturation indices was evaluated using multivariable linear regression models. BMI was positively associated with the relative concentration of saturated fatty acids (SFAs) (&beta, = 0.94, q-val = 0.001), and with palmitoleic, dihomo-&gamma, linolenic (DGLA), arachidonic (AA) and &alpha, linolenic acids, and was inversely associated with oleic, gondoic, trans-vaccenic, linoleic and &gamma, linolenic acids. Total fat percentage was positively associated with DGLA and AA, and inversely with linoleic and &gamma, linolenic acids. Low relative concentrations of some SFAs and high levels of n-6 PUFAs were associated with greater waist circumference. While the oleic/stearic and AA/DGLA acid ratios were inversely associated with BMI, DGLA/linoleic acid ratio was positively related to almost all variables. In addition to BMI, total fat percentage and waist circumference were also associated with certain individual fatty acids.

[EN] Background: The role of fatty acids (FAs) on mammographic density (MD) is unclear, and available studies are based on self-reported dietary intake. Objectives: This study assessed the association between specific serum phospholipid fatty acids (PLFAs) and MD in premenopausal women. Methods: The cross-sectional study DDM-Madrid recruited 1392 Spanish premenopausal women, aged 39-50 y, who attended a screening in a breast radiodiagnosis unit of Madrid City Council. Women completed lifestyle questionnaires and FFQs. Percentage MD was estimated using a validated computer tool (DM-Scan), and serum PLFA percentages were measured by GC-MS. Multivariable linear regression models were used to quantify the association of FA tertiles with MD. Models were adjusted for age, education, BMI, waist circumference, parity, oral contraceptive use, previous breast biopsies, and energy intake, and they were corrected for multiple testing. Results: Women in the third tertile of SFAs showed significantly higher MD compared with those in the first tertile (beta(T3vsT1) = 7.53; 95% CI: 5.44, 9.61). Elevated relative concentrations of palmitoleic (beta(T3vsT1) = 3.12; 95% CI: 0.99, 5.25) and gondoic (beta(T3vsT1) = 2.67; 95% CI: 0.57, 4.77) MUFAs, as well as high relative concentrations of palmitelaidic (beta(T3vsT1) = 5.22; 95% CI: 3.15, 7.29) and elaidic (beta(T3vsT1) = 2.69; 95% CI: 0.59, 4.79) trans FAs, were also associated with higher MD. On the contrary, women with elevated relative concentrations of n-6 (omega-6) linoleic (beta(T3vsT1) = -5.49; 95% CI; -7.62, -3.35) and arachidonic (beta(T3vsT1) = -4.68; 95% CI: -6.79, -2.58) PUFAs showed lower MD. Regarding desaturation indices, an elevated palmitoleic to palmitic ratio and a low ratio of oleic to steric and arachidonic to dihomo. gamma-linolenic acids were associated with higher MD. Conclusions: Spanish premenopausal women with high relative concentrations of most SFAs and some MUFAs and trans FAs showed an increased MD, whereas those with high relative concentrations of some n-6 PUFAs presented lower density. These results, which should be confirmed in further studies, underscore the importance of analyzing serum FAs individually., This study was funded by the Carlos III Institute of Health (AESI PI15CIII/0029). The article presents independent research. The views expressed are those of the authors and not necessarily those of the Carlos III Institute of Health.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by an autoimmune response in the joints and an exacerbation of cytokine responses. A minority of patients with RA experience spontaneous remission, but most will show moderate/high disease activity, with aggressive joint damage and multiple systemic manifestations. There is thus is a great need to identify prognostic biomarkers for disease risk to improve diagnosis and prognosis, and to inform on the most appropriate therapy. Here we focused on suppressor of cytokine signaling 1 (SOCS1), a physiological negative regulator of cytokines that modulates cell activation. Using four independent cohorts of patients with arthritis, we characterized the correlation between SOCS1 mRNA levels and clinical outcome. We found a significant inverse correlation between SOCS1 mRNA expression and disease activity throughout the follow-up of patients with RA. Lower baseline SOCS1 levels were associated with poorer disease control in response to methotrexate and other conventional synthetic disease-modifying anti-rheumatic drugs in early arthritis, and to rituximab in established (active) RA. Moreover, we identified several single nucleotide polymorphisms in the SOCS1 gene that correlated with SOCS1 mRNA expression, and that might identify those patients with early arthritis that fulfill RA classification criteria. One of them, rs4780355, is in linkage disequilibrium with a microsatellite (TTTTC)3−5, mapped 0.9 kb downstream of the SNP, and correlated with reduced SOCS1 expression in vitro. Overall, our data support the association between SOCS1 expression and disease progression, disease severity and response to treatment in RA. These observations underlie the relevance of SOCS1 mRNA levels for stratifying patients prognostically and guiding therapeutic decisions.

Chemokines and their receptors take part in many physiological and pathological processes, and their dysregulated expression is linked to chronic inflammatory and autoimmune diseases, immunodeficiencies, and cancer. The chemokine receptors, members of the G protein-coupled receptor family, are integral membrane proteins, with seven-transmembrane domains that bind the chemokines and transmit signals through GTP-binding proteins. Many assays used to study the structure, conformation, or activation mechanism of these receptors are based on ligand-binding measurement, as are techniques to detect new agonists and antagonists that modulate chemokine function. Such methods require labeling of the chemokine and/or its receptor, which can alter their binding characteristics. Surface plasmon resonance (SPR) is a powerful technique for analysis of the interaction between immobilized receptors and ligands in solution, in real time, and without labeling. SPR measurements nonetheless require expression and purification steps that can alter the conformation, stability, and function of the chemokine and/or the chemokine receptor. In this review, we focus on distinct methods to immobilize chemokine receptors on the surface of an optical biosensor. We expose the advantages and disadvantages of different protocols used and describe in detail the method to retain viral particles as receptor carriers that can be used for SPR determinations.

José Luis Izquierdo, Arturo Martínez, Elizabet Guzmán, Pilar de Lucas, José Miguel RodríguezPulmonology Department, Hospital Universitario, Guadalajara, Spain; Pulmonology Department, Hospital Gregorio Marañón, Madrid, SpainAbstract: The aim of our study is to determine whether chronic obstructive pulmonary disease (COPD) is an independent risk factor for ischemic heart disease and whether this association is related with a greater prevalence of classical cardiovascular risk factors. Ours is a case-control cross-sectional study design. Cases were hospital patients with ischemic heart disease in stable phase, compared with control hospital patients. All patients underwent post-bronchodilator (PBD) spirometry, a standardized questionnaire, and blood analysis. COPD was defined as per GOLD PBD forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) < 0.70. In our series of patient cases (n = 204) and controls (n = 100), there were 169 men in the case group (83%) and 84 in the control group (84%). Ages were 67 and 64 years, respectively (P < 0.05). There were no significant differences by weight, body mass index (BMI), pack-years, leukocytes, or homocysteine. The abdominal perimeter was significantly greater in cases (mean 101 cm ± standard deviation [SD] 10 versus 96 cm ± 11; P < 0.000). Both groups also had significant differences by C-reactive protein (CRP), fibrinogen, and hemoglobin values. In univariate analysis, increased risks for cases to show with individual classical cardiovascular risk factors were seen, with odds ratio (OR) 1.86 and 95% confidence interval (CI) (1.04–3.33) for diabetes mellitus, dyslipidemia (OR 2.10, 95% CI: 1.29–3.42), arterial hypertension (OR 2.47, 95% CI: 1.51–4.05), and increased abdominal perimeter (OR 1.71, 95% CI: 1.06–2.78). Percent predicted PBD FEV1 was 97.6% ± 23% in the patient group and 104% ± 19% in the control group (P = 0.01), but the prevalence of COPD was 24.1% in cases and 21% in controls. Therefore, COPD was not associated with ischemic heart disease: at the crude level (OR 1.19, 95% CI: 0.67–2.13) or after adjustment (OR 1.14, 95% CI:0.57–2.29). In conclusion, COPD was not associated with ischemic heart disease. The greater prevalence of classical cardiovascular risk factors in COPD patients could explain the higher occurrence of ischemic heart disease in these patients.Keywords: chronic obstructive pulmonary disease, cardiovascular disease, systemic inflammation, comorbidity