Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory ...responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33-driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33-mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33-driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.
Men and women differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections. Mechanisms responsible for this sexual dimorphism are still poorly ...documented and probably multifactorial. This review discusses the recent development in our understanding of the cell-intrinsic actions of biological factors linked to sex, sex hormones and sex chromosome complement, on immune cells, which may account for the sex differences in the enhanced susceptibility of women to develop immunological disorders, such as allergic asthma or systemic lupus erythematosus (SLE). We choose to more specifically discuss the impact of sex hormones on the development and function of immune cell populations directly involved in type-2 immunity, and the role of the X-linked Toll like receptor 7 (TLR7) in anti-viral immunity and in SLE. We will also elaborate on the recent evidence demonstrating that TLR7 escapes from X chromosome inactivation in the immune cells of women, and how this may contribute to endow woman immune system with enhanced responsiveness to RNA-virus and susceptibility to SLE.
Intestinal CD103+ DC promote the differentiation of Foxp3+ Treg from naïve CD4+ T cells through mechanisms involving TGF‐β and the dietary metabolite, retinoic acid (RA). In this study, we have ...analysed whether the specialised features of CD103+ DC are conserved in colitis. Our results show that inflammation dampens the tolerogenic properties of MLN CD103+ DC, which is associated with lower expression of tgfβ2 and aldh1a2. Accordingly, CD103+ DC taken from colitic mice are impaired in their ability to induce Foxp3+ Treg and instead favour the emergence of IFN‐γ‐producing CD4+ T cells compared with their steady‐state counterparts. BrdU‐labelling studies and analysis of ontogeny markers show that CD103+ DC from steady‐state and colitic settings retain similar subset composition and developmental pathways. These results indicate that MLN CD103+ DC are not hard‐wired to promote tolerance but can adapt to environmental conditions. The inflammatory properties of MLN CD103+ DC in colitic mice may reflect defective gut tolerogenic conditioning or altered migratory pathways and raise the possibility that migratory DC populations contribute to the pathogenesis of inflammatory bowel disease.
Most animals display multiple behavioral states and control the time allocation to each of their activity phases depending on their environment. Here we develop a new quantitative method to analyze ...Caenorhabditis elegans behavioral states. We show that the dwelling and roaming two-state behavior of C. elegans is tightly controlled by the concentration of food in the environment of the animal. Sensory perception through the amphid neurons is necessary to extend roaming phases while internal metabolic perception of food nutritional value is needed to induce dwelling. Our analysis also shows that the proportion of time spent in each state is modulated by past nutritional experiences of the animal. This two-state behavior is regulated through serotonin as well as insulin and TGF-beta signaling pathways. We propose a model where food nutritional value is assessed through internal metabolic signaling. Biogenic amines signaling could allow the worm to adapt to fast changes in the environment when peptide transcriptional pathways may mediate slower adaptive changes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infectious diseases, autoimmune diseases, and also allergy differentially affect women and men. In general, women develop strongest immune responses and thus the proportion of infected individuals ...and the severity of many viral, bacterial, or parasitic infections are increased in men. However, heightened immunity in women makes them more susceptible than men to autoimmunity and allergy. While sex differences in immunity are well documented, little is known about the cellular and molecular mechanisms underlying these immunological differences, particularly in allergic asthma. Asthma is a chronic inflammation of the airways mediated by exacerbated type 2 immune responses. Sex differences have been reported in the incidence, prevalence, and severity of asthma. While during childhood, males are more susceptible to asthma than females, there is a switch at the onset of puberty as for many other allergic diseases. This decrease of asthma incidence around puberty in males suggests that hormonal mediators could play a protective role in the susceptibility to allergic responses in male. Group 2 innate lymphoid cells (ILC2s) have recently emerged as critical players in the initiation of allergic responses, but also in the resolution of parasitic infection, through their capacity to rapidly and potently produce type 2 cytokines. This review will cover the current understanding of the impact of sex-linked factors in allergic inflammation, with a particular focus on the role of sex hormones on the development and function of tissue-resident ILC2s.
Innate lymphoid cell (ILC) subsets at barrier surfaces contribute to maintain tissue homeostasis and appropriate responses to infection. ILCs respond to environmental factors produced by ...non-hematopoietic cells within tissues, but also circulating cytokines or dietary compounds which allow them to adapt to organ milieu. Among these extrinsic signals, evidence is emerging that sex steroid hormones may act in a cell-intrinsic manner to regulate the development, maintenance in tissues and effector functions of specific subsets of ILCs. Understanding the nature and molecular mechanisms of sex steroid hormone actions on ILCs is important to unravel the cause of sexual disparity in human diseases and could lead to new drug development for the treatment of chronic inflammatory diseases or cancers. This review discusses the recent development in our understanding of the cell-intrinsic actions of sex steroid hormones on ILCs and their consequences on tissue-specific immunity with a particular focus on group 2 innate lymphoid cells and NK cells.
Type I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) occurs during viral infection, in response to Toll-like receptor 7 (TLR7) stimulation and is more vigorous in females than ...in males. Whether this sex bias persists in ageing people is currently unknown. In this study, we investigated the effect of sex and aging on IFN-α production induced by PRR agonist ligands.
In a large cohort of individuals from 19 to 97 years old, we measured the production of IFN-α and inflammatory cytokines in whole-blood upon stimulation with either R-848, ODN M362 CpG-C, or cGAMP, which activate the TLR7/8, TLR9 or STING pathways, respectively. We further characterized the cellular sources of IFN-α.
We observed a female predominance in IFN-α production by pDCs in response to TLR7 or TLR9 ligands. The higher TLR7-driven IFN-α production in females was robustly maintained across ages, including the elderly. The sex-bias in TLR9-driven interferon production was lost after age 60, which correlated with the decline in circulating pDCs. By contrast, STING-driven IFN-α production was similar in both sexes, preserved with aging, and correlated with circulating monocyte numbers. Indeed, monocytes were the primary cellular source of IFN-α in response to cGAMP.
We show that the sex bias in the TLR7-induced IFN-I production is strongly maintained through ages, and identify monocytes as the main source of IFN-I production via STING pathway.
This work was supported by grants from Région Occitanie/Pyrénées-Méditerranée (#12052910, Inspire Program #1901175), University Paul Sabatier, and the European Regional Development Fund (MP0022856).
Background: Despite the wide development of 90Y-loaded microspheres, 188Re-labeled lipiodol is still being used for radioembolization of hepatocellular carcinoma (HCC). However, the use of this ...latter compound is limited by in vivo instability. This study sought to evaluate the safety, bio-distribution, and response to 188Re-SSS lipiodol, a new and more stable compound. Method: Lip-Re-01 was an activity-escalation Phase 1 study involving HCC patients progressing after sorafenib. The primary endpoint was safety based on Common Terminology Criteria for Adverse Events (AEs) of Grade ≥3 within 2 months. Secondary endpoints included bio-distribution assessed by scintigraphy quantification from 1 to 72 h, tumor to non-tumor uptake ratio (T/NT), as well as blood, urine and feces collection over 72 h, dosimetry, and response evaluation (mRECIST). Results: Overall, 14 heavily pre-treated HCC patients were treated using a whole liver approach. The mean injected activity was 1.5 ± 0.4 GBq for activity Level 1 (n = 6), 3.6 ± 0.3 GBq for Level 2 (n = 6), and 5.0 ± 0.4 GBq for Level 3 (n = 2). Safety was acceptable with only 1/6 of Level 1 and 1/6 of Level 2 patients experiencing limiting toxicity (one liver failure; one lung disease). The study was prematurely discontinued unrelated to clinical outcomes. Uptake occurred in the tumor, liver, and lungs, and only sometimes in the bladder. The T/NT ratio was high with a mean of 24.9 ± 23.4. Cumulative urinary elimination and fecal eliminations at 72 h were very low, 4.8 ± 3.2% and 0.7 ± 0.8%, respectively. Partial response occurred in 21% of patients (0% in the first activity level; 37.5% in the others). Conclusion: The high in vivo stability of 188Re-SSS lipiodol was confirmed, resulting in encouraging responses for a Phase 1 study. As the 3.6 GBq activity proved to be safe, it will be used in a future Phase 2 study.
En France, l’asthme allergique touche 10 % de la population enfantine et 6 % de la population adulte avec des disparités de sexe. Alors que l’asthme est plus fréquent chez les garçons de la naissance ...à la puberté, il s’aggrave et devient plus répandu chez les femmes après l’adolescence. Les cellules lymphoïdes innées du groupe 2 (ILC2) sont récemment apparues comme des médiateurs centraux de l’asthme allergique du fait de leur capacité à promouvoir l’immunité adaptative de type 2. Nous avons mis en évidence dans un précédent article, dans des modèles murins, que les androgènes, naturellement présents en grande quantité chez les mâles, diminuent le nombre et les fonctions des ILC2 pulmonaires. Ce biais de sexe dans le nombre d’ILC2 pourrait participer à expliquer la moindre susceptibilité des mâles à développer un asthme allergique.Nous avons ici cherché à évaluer si un traitement de courte durée avec des androgènes peut influencer le nombre des ILC2 ainsi que l’inflammation pulmonaire chez des souris mâles 1.Nous montrons que les ILC2 pulmonaires expriment un récepteur aux androgènes (AR) fonctionnel qui peut être ciblé in vivo par des androgènes exogènes. Un court traitement avec des androgènes est capable d’inhiber la prolifération et la production de cytokines par les ILC2. Ce traitement est associé à une diminution de l’inflammation pulmonaire induite par l’administration d’allergènes. De manière inattendue, et alors que son expression est augmentée par les androgènes, notre étude exclue un rôle pour le récepteur inhibiteur KLRG1 dans l’inhibition de l’asthme par les hormones mâles.Cette étude apporte la preuve de concept qu’un traitement ciblant le récepteur aux androgènes dans les ILC2s, y compris chez les souris femelles, peut jouer un rôle bénéfique dans l’asthme allergique, renforçant la notion émergente du rôle protecteur des androgènes dans cette pathologie.
Background
Endogenous opioids, including enkephalins, are fundamental regulators of pain. In inflammatory conditions, the local release of opioids by leukocytes at the inflammatory site inhibits ...nociceptor firing, thereby inducing analgesia. Accordingly, in chronic intestinal T
h
1/T
h
17-associated inflammation, enkephalins released by colitogenic CD4
+
T lymphocytes relieve inflammation-induced visceral pain. The present study aims to investigate whether mucosal T-cell-derived enkephalins also exhibit a potent anti-inflammatory activity as described for exogenous opioid drugs in T
h
1/T
h
17-associated colitis.
Methods
The anti-inflammatory effects of endogenous opioids were investigated in both T
h
1/T
h
17-associated (transfer of CD4
+
CD45RB
high
T lymphocytes) and T
h
2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4
+
T cell subsets were compared in mice treated or not treated with naloxone methiodide, a peripheral antagonist of opioid receptors. The anti-inflammatory activity of T-cell-derived enkephalins was further estimated by comparison of colitis severity in immunodeficient mice into which naïve CD4
+
CD45RB
high
T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred.
Results
Peripheral opioid receptor blockade increases the severity of T
h
1/T
h
17-induced colitis and attenuates T
h
2 oxazolone colitis. The opposite effects of naloxone methiodide treatment in these two models of intestinal inflammation are dependent on the potency of endogenous opioids to promote a T
h
2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4
+
CD45RB
high
T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury.
Conclusions
Endogenous opioids, including T-cell-derived enkephalins, promote a T
h
2-type immune response, which, depending on the context, may either attenuate (T
h
1/T
h
17-associated) or aggravate (T
h
2-associated) intestinal inflammation.
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