Manipulating leukocyte interactions in vivo through optogenetic chemokine release.

Light-mediated release of signaling ligands, such as chemoattractants, growth factors, and cytokines is an attractive strategy for investigation and therapeutic targeting of leukocyte communication and immune responses. We introduce a versatile optogenetic method to control ligand secretion, combining UV-conditioned endoplasmic reticulum-to-Golgi trafficking and a furin-processing step. As proof of principle, we achieved light-triggered chemokine secretion and demonstrated that a brief pulse of chemokine release can mediate a rapid flux of leukocyte contacts with target cells in vitro and in vivo. This approach opens new possibilities for dynamic investigation of leukocyte communication in vivo and may confer the potential to control the local release of soluble mediators in the context of immune cell therapies.This work was supported by Institut Pasteur, INSERM, the European Research Council (starting grant LymphocyteContacts) (P.B.), and the Medical Research Council (RG73189) (M.S.)

Induction, Propagation, and Activity of Host Nitric Oxide: Lessons from Leishmania Infection

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Work-Related Stressors and Increased Risk of Benzodiazepine Long-Term Use Findings From the CONSTANCES Population-Based Cohort

International audienceObjectives. To examine whether stressful job exposure to the public could be associated with having long-term benzodiazepine use. Methods. From the participants included between 2012 and 2016 in the French population-based CONSTANCES cohort, 13 934 men and 19 261 women declared a daily job exposure to the public and rated the frequency of stressful exposure. We examined benzodiazepine long-term use by using drug reimbursement administrative registries. Logistic regressions provided odds ratios (ORs) of benzodiazepine long-term use, with stratification for gender and adjustment for age, education, and area deprivation index. Occupational grade, job strain, depression, self-rated health, and alcohol use disorder were additional stratification variables. Results. Benzodiazepine long-term use was positively associated with stressful exposure to the public ("often or always" vs "rarely or never") in men (OR = 2.2; 95% confidence interval [CI] = 1.8, 2.8) and women (OR = 1.6; 95% CI = 1.4, 1.9), with dose-dependent relationships (P trends <.001). Adjustments and analyses in subgroups without other individual or environmental vulnerability factors led to similar results. Conclusions. Stressful job exposure to the public increases the risk of benzodiazepine long-term use. Prevention programs aiming at reducing the burden of benzodiazepine longterm use would benefit in targeting this specific population

Depression, Cognitive Functions, and Impaired Functioning in Middle-Aged Adults From the CONSTANCES Cohort

International audienceOBJECTIVE:This large-scale population-based prospective study examined the association between depressive symptoms and cognitive performance at baseline with later functioning in middle-aged adults.METHODS:The Center for Epidemiologic Studies Depression Scale, the Digit Symbol Substitution Test (DSST), the Trail Making Test B (TMT-B), and the Semantic Verbal Fluency test (SVF) were completed at baseline by 7,426 participants aged ≥ 45 years from February 2012 to December 2013. Role limitations and social functioning were later assessed with the second version of the 12-Item Short Form Health Survey. The association between depressive symptoms and cognitive performance at baseline with functioning at follow-up was examined using general linear models and mediation analyses including sex, age, education, alcohol intake, and cannabis use as covariates.RESULTS:Altered functioning at follow-up was predicted by depressive symptoms (β per standard deviation [95% confidence intervals]: -1.10 [-1.16 to -1.03] and -1.02 [-1.08, -0.96] for role limitations and social functioning, respectively) and DSST, TMT-B, and SVF performance (for role limitations: 0.11 [0.09 to 0.14], -0.11 [-0.13 to -0.08], and 0.03 [0.01 to 0.06], respectively; for social functioning: 0.10 [0.07 to 0.12], -0.08 [-0.11 to -0.06], and 0.04 [0.01 to 0.05], respectively) at baseline. Depressive symptoms were associated with poorer cognitive performance at baseline (-0.19 [-0.25 to -0.13], 0.15 [0.08 to 0.21], and -0.11 [-0.17 to -0.04], respectively). Cognitive performance accounted for only 0.3%-1.4% of the relationship between depressive symptoms and functioning. In contrast, depressive symptoms accounted for 19.5%-43.7% of the association between cognitive performance and functioning.CONCLUSIONS:In middle-aged adults from the general population, cognitive impairment is unlikely to substantially explain the association between depressive symptoms and later role limitations and social functioning

Acceptability of Second-Line Antidepressant Medications Using Filled Prescription Sequences in a Nationwide Cohort Study

International audienceBackground: Although about half of patients do not respond to a first-line antidepressant medication, there is no consensus on the best second-line option. The aim of this nationwide population-based study was to rank antidepressants according to their relative acceptability (ie, efficacy and tolerability) using filled prescription sequences after failure of first treatment. Methods: About 1.2 million people were identified as new antidepressant users in the French national health data system in 2011. The inclusion criterion was having at least 2 filled prescriptions of a second-line treatment after a filled prescription of a first-line treatment, resulting in 63,726 participants. The outcome was clinical acceptability as measured by the continuation/change ratio for second-line treatment. Continuation sequence was defined as at least 2 refills of the same treatment. Change sequence was defined as at least 1 filled prescription of another antidepressant. Adjusted odds ratios (aORs) were computed through multivariable binary logistic regressions. Results: Intraclass switch had a better acceptability than interclass switch (aOR [95% CI]: 1.23 [1.20-1.28]). According to the first-line treatment, intraclass switch remained more acceptable for selective serotonin reuptake inhibitors only (1.37 [1.31-1.42]). For α2 blockers and tricyclic agents, combination antidepressant therapy was the most acceptable second-line option (1.59 [1.27-2.01] and 2.53 [1.53-4.04], respectively), whereas for serotonin-norepinephrine reuptake inhibitors there was no significant difference between the strategies. For other antidepressants, intraclass switch had lower acceptability than interclass switch (0.70 [0.51-0.95]). Conclusions: Administrative claim databases may help with ranking acceptability of second-line treatments in real world settings and complement randomized controlled trials in informing clinicians about the most acceptable second-line options according to the first-line treatment

Using filled prescription sequences to rank antidepressants according to their acceptability in the general population: The Constances cohort

International audienceRanking antidepressants according to their acceptability (i.e. a combination of both efficacy and tolerability) in the general population may help choosing the best first-line medication. This study aimed to rank antidepressants according to the proportion of filled prescription sequences consistent with a continuation of the first treatment versus those consistent with a change. A first step was validating this measure as a proxy of acceptability by examining the association of these two kinds of sequences with levels of depressive symptoms. Among 64,467 individuals included in the French population-based Constances cohort, reimbursements of antidepressants from January 2009 to December 2015 were extracted from the French national health insurance system claims database. Depressive symptoms were measured at inclusion with the Center for Epidemiologic Studies-Depression scale (CES-D). Between January 2010 and December 2015, 6675 participants newly initiated an antidepressant (34.5% men, mean (SD) age: 48.3 (12.1) years). Among the subsample of participants included during the six-month period following treatment initiation, individuals with continuation sequences had lower levels of depressive symptoms than those with change sequences (mean (SE) CES-D score: 18.9 (0.8) versus 26.5 (2.1), p < 0.001). According to the continuation/change ratio observed over this six-month period in all participants, escitalopram ranked first, followed by sertraline, venlafaxine, citalopram, fluoxetine and paroxetine. In an independent replication sample representative of the French national population, the same six medications ranked first, with escitalopram remaining in first place. The proportion of filled prescription sequences consistent with a continuation versus a change of the first prescribed treatment may provide a widely available measure of antidepressant acceptability in community practice

A metabolism-based quorum sensing mechanism contributes to termination of inflammatory responses

International audienceRecruitment of immune cells with antimicrobial activities is essential to fight local infections but has the potential to trigger immunopathology. Whether the immune system has the ability to sense inflammation intensity and self-adjust accordingly to limit tissue damage remains to be fully established. During local infection with an intracellular pathogen, we have shown that nitric oxide (NO) produced by recruited monocyte-derived cells was essential to limit inflammation and cell recruitment. Mechanistically, we have provided evidence that NO dampened monocyte-derived cell cytokine and chemokine production by inhibiting cellular respiration and reducing cellular ATP:ADP ratio. Such metabolic control operated at the tissue level but only when a sufficient number of NO-producing cells reached the site of infection. Thus, NO production and activity act as a quorum sensing mechanism to help terminate the inflammatory response

Photoconvertible Pathogen Labeling Reveals Nitric Oxide Control of Leishmania major Infection In Vivo via Dampening of Parasite Metabolism

International audienceThe immune system can control infectious diseases through different modes of action, including direct killing or spatial confinement. Addressing how the immune system impacts pathogen biology in vivo has remained challenging. We expressed a photoconvertible fluorescent protein in pathogens in order to track their spatial dissemination in infected tissues. In addition, we developed the fluorescence recovery after photoconversion (FRAC) method in order to probe pathogen metabolic activity in vivo. Combining these two approaches in the context of Leishmania major infection of mice and pharmacologically inhibiting iNOS, we found that nitric oxide produced during the immune response to L. major reduces the metabolic activity of intracellular parasites without necessarily exerting direct killing. We propose that this chronic pressure on pathogen proliferation represents a sublethal mode of control required for ultimately resolving the infection. The ability to probe pathogen biology in response to immune defense mechanisms in vivo should create opportunities for better dissecting host-pathogen interactions