438 research outputs found
Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia
Respiratory viral infections are associated with an increased risk of asthma, but how acute Th1 antiviral immune responses lead to chronic inflammatory Th2 disease remains undefined. We define a novel pathway that links transient viral infection to chronic lung disease with dendritic cell (DC) expression of the high-affinity IgE receptor (FcΔRIα). In a mouse model of virus-induced chronic lung disease, in which Sendai virus triggered a switch to persistent mucous cell metaplasia and airway hyperreactivity after clearance of replicating virus, we found that FceRIaâ/â mice no longer developed mucous cell metaplasia. Viral infection induced IgE-independent, type I IFN receptorâdependent expression of FcΔRIα on mouse lung DCs. Cross-linking DC FcΔRIα resulted in the production of the T cell chemoattractant CCL28. FceRIaâ/â mice had decreased CCL28 and recruitment of IL-13âproducing CD4+ T cells to the lung after viral infection. Transfer of wild-type DCs to FceRIaâ/â mice restored these events, whereas blockade of CCL28 inhibited mucous cell metaplasia. Therefore, lung DC expression of FcΔRIα is part of the antiviral response that recruits CD4+ T cells and drives mucous cell metaplasia, thus linking antiviral responses to allergic/asthmatic Th2 responses
Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals
Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Rα2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia
Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia
Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases
BackgroundPro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögrenâs syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases.MethodsWe profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes.FindingsTwo shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation.ConclusionsThis work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.FundingGrant from F. Hoffmann-La Roche (Roche) AG
Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases
BackgroundPro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögrenâs syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases.MethodsWe profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes.FindingsTwo shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation.ConclusionsThis work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.FundingGrant from F. Hoffmann-La Roche (Roche) AG
The Bacterial Preparation OK432 Induces IL-12p70 Secretion in Human Dendritic Cells in a TLR3 Dependent Manner
Dendritic cells (DC) used in therapeutic cancer immunotherapy have to be able to stimulate T cells resulting in an immune response that can efficiently target the cancer cells. One of the critical hurdles has been the lack of IL-12p70 production when maturating the DC, which is rectified by using the bacterial preparation OK432 (trade name Picibanil) to mature the cells. In order to identify the mechanism behind OK432 stimulation of DC, we investigated the contribution of different TLR to examine their involvement in IL-12p70 production. By combining different inhibitors of TLR signaling, we demonstrate here that TLR3 is responsible for the IL-12p70 production of DC induced by OK432. Moreover, our data suggest that the ligand triggering IL-12p70 secretion upon TLR3 stimulation is sensitive to proteinase and partly also RNAse treatment. The fact that a bacterial compound like OK432 can activate the TLR3 pathway in human DC is a novel finding. OK432 demonstrates a critical ability to induce IL-12p70 production, which is of great relevance in DC based cancer immunotherapy
Population of Merging Compact Binaries Inferred Using Gravitational Waves through GWTC-3
We report on the population properties of compact binary mergers inferred from gravitational-wave observations of these systems during the first three LIGO-Virgo observing runs. The Gravitational-Wave Transient Catalog 3 (GWTC-3) contains signals consistent with three classes of binary mergers: binary black hole, binary neutron star, and neutron star-black hole mergers. We infer the binary neutron star merger rate to be between 10 and 1700 Gpc-3 yr-1 and the neutron star-black hole merger rate to be between 7.8 and 140 Gpc-3 yr-1, assuming a constant rate density in the comoving frame and taking the union of 90% credible intervals for methods used in this work. We infer the binary black hole merger rate, allowing for evolution with redshift, to be between 17.9 and 44 Gpc-3 yr-1 at a fiducial redshift (z=0.2). The rate of binary black hole mergers is observed to increase with redshift at a rate proportional to (1+z)Îș with Îș=2.9-1.8+1.7 for zâČ1. Using both binary neutron star and neutron star-black hole binaries, we obtain a broad, relatively flat neutron star mass distribution extending from 1.2-0.2+0.1 to 2.0-0.3+0.3Mâ. We confidently determine that the merger rate as a function of mass sharply declines after the expected maximum neutron star mass, but cannot yet confirm or rule out the existence of a lower mass gap between neutron stars and black holes. We also find the binary black hole mass distribution has localized over- and underdensities relative to a power-law distribution, with peaks emerging at chirp masses of 8.3-0.5+0.3 and 27.9-1.8+1.9Mâ. While we continue to find that the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above approximately 60Mâ, which would indicate the presence of a upper mass gap. Observed black hole spins are small, with half of spin magnitudes below Ïiâ0.25. While the majority of spins are preferentially aligned with the orbital angular momentum, we infer evidence of antialigned spins among the binary population. We observe an increase in spin magnitude for systems with more unequal-mass ratio. We also observe evidence of misalignment of spins relative to the orbital angular momentum
The population of merging compact binaries inferred using gravitational waves through GWTC-3
We report on the population properties of 76 compact binary mergers detected with gravitational waves below a false alarm rate of 1 per year through GWTC-3. The catalog contains three classes of binary mergers: BBH, BNS, and NSBH mergers. We infer the BNS merger rate to be between 10 and 1700 and the NSBH merger rate to be between 7.8 and 140 , assuming a constant rate density versus comoving volume and taking the union of 90% credible intervals for methods used in this work. Accounting for the BBH merger rate to evolve with redshift, we find the BBH merger rate to be between 17.9 and 44 at a fiducial redshift (z=0.2). We obtain a broad neutron star mass distribution extending from to . We can confidently identify a rapid decrease in merger rate versus component mass between neutron star-like masses and black-hole-like masses, but there is no evidence that the merger rate increases again before 10 . We also find the BBH mass distribution has localized over- and under-densities relative to a power law distribution. While we continue to find the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above . The rate of BBH mergers is observed to increase with redshift at a rate proportional to with for . Observed black hole spins are small, with half of spin magnitudes below . We observe evidence of negative aligned spins in the population, and an increase in spin magnitude for systems with more unequal mass ratio
All-sky search for long-duration gravitational-wave bursts in the third Advanced LIGO and Advanced Virgo run
After the detection of gravitational waves from compact binary coalescences, the search for transient gravitational-wave signals with less well-defined waveforms for which matched filtering is not well suited is one of the frontiers for gravitational-wave astronomy. Broadly classified into âshortâ âČ1ââs and âlongâ âł1ââs duration signals, these signals are expected from a variety of astrophysical processes, including non-axisymmetric deformations in magnetars or eccentric binary black hole coalescences. In this work, we present a search for long-duration gravitational-wave transients from Advanced LIGO and Advanced Virgoâs third observing run from April 2019 to March 2020. For this search, we use minimal assumptions for the sky location, event time, waveform morphology, and duration of the source. The search covers the range of 2â500 s in duration and a frequency band of 24â2048 Hz. We find no significant triggers within this parameter space; we report sensitivity limits on the signal strength of gravitational waves characterized by the root-sum-square amplitude hrss as a function of waveform morphology. These hrss limits improve upon the results from the second observing run by an average factor of 1.8
Constraints on dark photon dark matter using data from LIGO's and Virgo's third observing run
We present a search for dark photon dark matter that could couple to
gravitational-wave interferometers using data from Advanced LIGO and Virgo's
third observing run. To perform this analysis, we use two methods, one based on
cross-correlation of the strain channels in the two nearly aligned LIGO
detectors, and one that looks for excess power in the strain channels of the
LIGO and Virgo detectors. The excess power method optimizes the Fourier
Transform coherence time as a function of frequency, to account for the
expected signal width due to Doppler modulations. We do not find any evidence
of dark photon dark matter with a mass between eV/, which corresponds to frequencies between 10-2000
Hz, and therefore provide upper limits on the square of the minimum coupling of
dark photons to baryons, i.e. dark matter. For the
cross-correlation method, the best median constraint on the squared coupling is
at eV/; for the
other analysis, the best constraint is at eV/. These limits improve upon those obtained
in direct dark matter detection experiments by a factor of for
eV/, and are, in absolute terms, the
most stringent constraint so far in a large mass range eV/.Comment: 20 pages, 7 figure
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