Allergic diseases including asthma, chronic rhinosinusitis, and atopic dermatitis are common conditions worldwide. While type 2 immune responses induced by T-cells significantly cause allergic ...inflammation, the recently identified group two innate lymphoid cells (ILC2s) are emerging as critical players in the development of allergy. Upon allergen exposure, ILC2s are rapidly activated by cytokines released by epithelial cells. Activated ILC2s release various effector cytokines altogether contributing to the pathogenesis of allergy and can even cause inflammation in the absence of T-cells, as observed in asthma. Although the factors inducing ILC2 activation have been identified, evidence suggests that multiple factors can enhance or repress ILC2 proliferation, trafficking, or secretion of effector cytokines upon allergic inflammation. In this review, we discuss the recent findings that influence ILC2 activation and the resulting effects on the pathogenesis of allergy. A better understanding of how ILC2s are modulated will open the door to the development of new therapeutic strategies against allergic diseases.
In this study, the natural convection enhancement in grooved vertical multi-cylinders at various groove geometries is investigated. The effects of several grooves ranging from 3 to 7, groove ...thickness ranging from 0.25 to 1 mm, and cylinder surface temperature ranging from 350 to 500 K at different Rayleigh numbers are examined. The current study was simulated using the finite volume method using CFD with a laminar steady-state condition. The SIMPLE scheme is used for the pressure–velocity coupling discretization and the second-order upwind method is utilized to discretize the momentum and energy equations. The results obtained from the present research show that the presence of grooves on the cylinders will increase the heat transfer surface, create and intensify the secondary flow and mixing, and ultimately increase the heat transfer. Moreover, by increasing the number of grooves and its thickness, the amount of heat transfer increases dramatically. It’s also found that the groove thickness parameter's effectiveness on heat transfer is more than the groove number parameter. Ultimately, it’s demonstrated that using grooved cylinders leads to a 14 % augmentation in Nusselt number in comparison with employing plain cylinders.
This paper presents a numerical simulation of nanofluid flowing in an open cavity under mixed convection by considering various heat transfer zones. To enhance the heat transfer, water was augmented ...with copper nanoparticles at different ϕ (volume fraction of nanoparticles) values. The present paper aims to determine the optimal position which maximizes the heat transfer in a circular open cavity. Also, in this research the investigation of combined convection flow in a specific geometry, taking into account the changes in the flow parameters, is an attempt to model the temperature field and heat transfer. For this purpose, the nanofluid flow for Reynolds numbers of Re =10, 50 and 100 is investigated. On the other hand, the hot areas in the curved part of the open cavity are separated in various cases. The results show that due to the low velocity of the fluid in the circular part of the cavity, especially in the hot wall area, most of the fluid exchange is due to natural convection due to density difference and the hot areas are strengthen the flow circulation. The exchange is also improved by increasing Re (Reynolds number) or the momentum term, and the distribution of T (temperature) in the cavity becomes more uniform. Hot spots with low heat transfer coefficient were attenuated at higher Re. The most suitable temperature distributions were achieved for W4 and W2. By increasing ϕ, the friction factor decreases for pure water, especially in W2 and W3. However, due to fluid-surface impact at Re = 100 in W2 and W3, the friction factor does not change significantly by altering ϕ. Using a higher Re and the dominance of the fluid momentum in comparison with the viscous force, the effect of nanoparticle concentration decreases. In general, the best heat transfer occurs at higher volume fraction of nanoparticles. Finally, at all Reynolds numbers, the heat transfer increases by 8–19%. This is because nanoparticles are added to pure water (working fluid).
This study deals with the numerical simulation in the case of natural convection of nanofluid flow within a semi-circular enclosure for the cooling of a silicon chip. Water/MWCNT nanofluid is ...included in cooling fluid in the volume fraction of nanoparticles 0 ≤ φ ≤ 6%. In this numerical study, natural convection of nanofluid flow is performed inside a semi-circular enclosure for cooling of an electronic chip using the Finite Volume Method (FVM). In this study, flow is simulated for Ra = 1 × 105, 1 × 106, 1 × 107, and 1 × 108. The findings confirm that increasing the Rayleigh number leads to the augmentation of the driver of fluid vortexes. Fluid motion with a higher route length (larger attack angle) leads to the intensity of flow domain motion which this intensity is more considerable by augmenting the Rayleigh number. The enhancement of attack angle regarding enclosure leads to strong fluid circulation and better flow rotation. The highest heat transfer distribution is seen in φ = 6% which in Ra = 1 × 108, it is more sensitive compared to Ra = 1 × 105. At the flow separation regions between two vortexes, the temperature increments due to the creation of an intermediate region. As the Rayleigh number is increased, due to the augmentation of fluid circulation, flow motion intensity goes up e and the separation regions of vortexes lead to strong changes in the friction factor graphs. The highest friction factor is created where fluid motion components are with higher changes or significant effects in the instance of the boundary layer of flow representing themselves in these regions. The created difference between the two sides of the Nusselt number graphs is due to the attack angle changes. The values of velocity and temperature gradients are the factors that lead to the increase of entropy.
Group 2 Innate lymphoid cells (ILC2) contribute significantly to allergic inflammation. However, the role of microbiota on ILC2s remains to be unraveled. Here we show that short chain fatty acids ...(SCFAs), such as butyrate, derived from fermentation of dietary fibers by the gut microbiota inhibit pulmonary ILC2 functions and subsequent development of airway hyperreactivity (AHR). We further show that SCFAs modulate GATA3, oxidative phosphorylation, and glycolytic metabolic pathways in pulmonary ILC2s. The observed phenotype is associated with increased IL-17a secretion by lung ILC2s and linked to enhanced neutrophil recruitment to the airways. Finally, we show that butyrate-producing gut bacteria in germ-free mice effectively suppress ILC2-driven AHR. Collectively, our results demonstrate a previously unrecognized role for microbial-derived SCFAs on pulmonary ILC2s in the context of AHR. The data suggest strategies aimed at modulating metabolomics and microbiota in the gut, not only to treat, but to prevent lung inflammation and asthma.
Regulatory T (Treg) cells are central to limit immune responses to allergens. Here we show that PD-L2 deficiency prevents the induction of tolerance to ovalbumin and control of airway ...hyperreactivity, in particular by limiting pTreg numbers and function. In vitro, PD-1/PD-L2 interactions increase iTreg numbers and stability. In mice lacking PD-L2 we find lower numbers of splenic pTregs at steady state, producing less IL-10 upon activation and with reduced suppressive activity. Remarkably, the numbers of splenic pTregs are restored by adoptively transferring PD-L2
dendritic cells to PD-L2
mice. Functionally, activated pTregs lacking PD-L2 show lower Foxp3 expression, higher methylation of the Treg-Specific Demethylation Region (TSDR) and a decreased Tricarboxylic Acid (TCA) cycle associated with a defect in mitochondrial function and ATP production. Consequently, pyruvate treatment of PD-L2
mice partially restores IL-10 production and airway tolerance. Together, our study highlights the importance of the PD-1/PD-L2 axis in the control of metabolic pathways regulating pTreg Foxp3 stability and suppressive functions, opening up avenues to further improve mucosal immunotherapy.
Ca
entry via Ca
release-activated Ca
(CRAC) channels is a predominant mechanism of intracellular Ca
elevation in immune cells. Here we show the immunoregulatory role of CRAC channel components Orai1 ...and Orai2 in Group 2 innate lymphoid cells (ILC2s), that play crucial roles in the induction of type 2 inflammation. We find that blocking or genetic ablation of Orai1 and Orai2 downregulates ILC2 effector function and cytokine production, consequently ameliorating the development of ILC2-mediated airway inflammation in multiple murine models. Mechanistically, ILC2 metabolic and mitochondrial homeostasis are inhibited and lead to the upregulation of reactive oxygen species production. We confirm our findings in human ILC2s, as blocking Orai1 and Orai2 prevents the development of airway hyperreactivity in humanized mice. Our findings have a broad impact on the basic understanding of Ca
signaling in ILC2 biology, providing potential insights into the development of therapies for the treatment of allergic and atopic inflammatory diseases.
Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated ...immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an immune checkpoint in different inflammatory diseases.
Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s.
Wild-type and LAIR-1 knockout mice were intranasally challenged with IL-33, and pulmonary ILC2s were sorted to perform an ex vivo comparative study based on RNA sequencing and flow cytometry. We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using knockout mice and adoptive transfer experiments in Rag2−/−Il2rg−/− mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s.
We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates cytokine secretion and effector function. LAIR-1 signaling in ILC2s was mediated via inhibitory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR in IL-33 and Alternaria alternata models. In adoptive transfer experiments, we confirmed the LAIR-1–mediated regulation of ILC2s in vivo. Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and knockdown approaches of Lair1 resulted in higher cytokine production. Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced ILC2-dependent AHR in a humanized ILC2 murine model.
Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.
Display omitted
IL-25 has been shown to induce Th2 responses and airway hyperreactivity (AHR) in mice, but the mechanism of action is not understood and it is unclear which cells mediate this disease. In this study ...we show that the receptor for IL-25, IL-17RB, is highly expressed on a subset of naive and activated CD4(+) invariant NKT (iNKT) cells, but not on activated T cells. IL-17RB(+) iNKT cells produced large amounts of Th2 cytokines that were substantially increased by IL-25 stimulation. Furthermore, IL-17RB(+) iNKT cells were capable of restoring AHR in iNKT cell-deficient mice, whereas IL-17RB(-) iNKT cells failed to reconstitute AHR and lung inflammation. Finally, IL-17RB(+) iNKT cells were detected in the lungs of wild-type mice, and induction of AHR by intranasal administration of IL-25 was significantly impaired in iNKT cell-deficient mice. Overall, our data suggest a critical role for iNKT cells in IL-25-mediated AHR. These results may lead to novel therapeutic approaches to target IL-17RB(+) iNKT cells for the treatment of allergic asthma.
PDF
