Allergens have been identified as potential triggers in patients with atopic dermatitis (AD). AD patients are highly sensitive to cockroach allergen. The underlying mechanism, however, remains undetermined. Here, we established a cockroach allergen-induced AD-like mouse model and demonstrated that repeated exposure to cockroach allergen led to aggravated mouse skin inflammation, characterized by increased type 2 immunity, type 2 innate lymphoid cells (ILC2s), and mast cells. Increased skin mast cells were also observed in AD patients. AD mice with mast cell-deficient mice (kitW-sh/W-sh) showed diminished skin inflammation, suggesting that mast cells are required in allergen-induced skin inflammation. Furthermore, dendritic cell immuno-receptor (DCIR) is up-regulated in skin mast cells of AD patients and mediates allergen binding and uptake. DCIR-/- mice or reconstituted kitW-sh/W-sh mice with DCIR-/- mast cells showed a significant reduction in AD-like inflammation. Both in vitro and in vivo analyses demonstrated that DCIR-/- mast cells had reduced IgE-mediated mast cell activation and passive cutaneous anaphylaxis. Mechanistically, DCIR regulates allergen-induced IgE-mediated mast cell ROS generation and oxidation of calmodulin kinase II (ox-CaMKII). ROS-resistant CaMKII (MM-VVδ) prevents allergen-induced mast cell activation and inflammatory mediator release. Our study reveals a previously unrecognized DCIR-ROS-CaMKII axis that controls allergen-induced mast cell activation and AD-like inflammation.
Xiaoyan Luo, Jingsi Chen, Huan Yang, Xinyue Hu, Martin P. Alphonse, Yingchun Shen, Yuko Kawakami, Xiaoying Zhou, Wei Tu, Toshiaki Kawakami, Mei Wan, Nathan K. Archer, Hua Wang, Peisong Gao
Following myocardial infarction (MI), elderly patients have a poorer prognosis which may belinked to increased coronary microvessel susceptibility to injury. Interleukin-36 (IL-36), anewly discovered pro-inflammatory member of the IL-1 superfamily, may mediate this injurybut its role in the injured heart is currently not known. We firstly demonstrated the presence of IL-36(α/β) and its receptor (IL-36R) in ischaemia-reperfusion (IR) injured mouse hearts and,interestingly, noted that expression of both increased with ageing. An intravital modelfor imaging the adult and aged IR injured beating heart in real-time in vivo was used todemonstrate heightened basal and injury-induced neutrophil recruitment, and poorer bloodflow, in the aged coronary microcirculation when compared to adult hearts. An IL-36Rantagonist (IL-36Ra) significantly decreased neutrophil recruitment, improved blood flow andreduced infarct size in both adult and aged mice. This may be mechanistically explained byattenuated endothelial oxidative damage and VCAM-1 expression in IL-36Ra treated mice.Our findings of an enhanced age-related coronary microcirculatory dysfunction inreperfused hearts may explain the poorer outcomes in elderly patients following MI. Sincetargeting the IL-36/IL-36R pathway was vasculoprotective in aged hearts, it may potentially be a therapy for treating MI in the elderly.
Juma El-Awaisi, Dean P.J. Kavanagh, Marco R. Rink, Chris J. Weston, Nigel E. Drury, Neena Kalia
Infants born prematurely worldwide have up to a 50% chance of developing Bronchopulmonary Dysplasia (BPD), a clinical morbidity characterized by dysregulated lung alveolarization and microvascular development. It is known that Platelet-Derived Growth Factor Receptor Alpha positive (PDGFRA+) fibroblasts are critical for alveolarization, and that PDGFRA+ fibroblasts are reduced in BPD. A better understanding of fibroblast heterogeneity and functional activation status during pathogenesis is required to develop mesenchymal-targeted therapies for BPD. In this study, we utilized a neonatal hyperoxia mouse model (90% O2 PN0-PN7) and performed studies on sorted PDGFRA+ cells during injury and room air recovery. After hyperoxia injury, PDGFRA+ matrix and myofibroblasts decrease and PDGFRA+ lipofibroblasts increase by transcriptional signature and population size. PDGFRA+ matrix and myofibroblast recover during repair (PN10). After 7 days of in vivo hyperoxia, PDGFRA+ sorted fibroblasts have reduced contractility in vitro, reflecting loss of myofibroblast commitment. Organoids made with PN7 PDGFRA+ fibroblasts from hyperoxia mice exhibit reduced alveolar type 1 cell differentiation, suggesting reduced alveolar niche-supporting PDGFRA+ matrix fibroblast function. Pathway analysis predicted reduced WNT signaling in hyperoxia fibroblasts. In alveolar organoids from hyperoxia exposed fibroblasts WNT activation by CHIR increased size and number of alveolar organoids and enhanced alveolar type 2 cell differentiation.
Matthew R. Riccetti, Mereena George Ushakumary, Marion Waltamath, Jenna Green, John Snowball, Sydney E. Dautel, Mehari Endale, Bonny Lami, Jason Woods, Shawn K. Ahlfeld, Anne-Karina T. Perl
The molecular mechanisms that drive the acquisition of distinct neural crest cell (NCC) fates is still poorly understood. Here, we identify Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating Cardiac NCCs (CNCCs). Using transcriptomic analysis, genetic and fate mapping approaches in transgenic mice, we show that disruption of Prdm6 is associated with impaired CNCC differentiation, delamination, and migration, and leads to patent ductus arteriosus (DA)and ventricular noncompaction. Bulk and single-cell RNA-seq analyses of DA and CNCC identify Prdm6 as a regulator of a network of CNCC specification genes including Wnt1, Tfap2b, and Sox9. Loss of Prdm6 in CNCCs diminishes its expression in pre-EMT cluster, resulting in the retention of NCC in the dorsal neural tube. This defect is associated with diminished H4K20 mono-methylation and G1-S progression and augmented Wnt1 transcript levels in pre-EMT and neural tube clusters, which we show is the major driver of the impaired CNCC migration. Altogether, these findings reveal Prdm6 as a key regulator of CNCC differentiation and migration and identify Prdm6 and its regulated network as potential targets for the treatment of congenital heart diseases.
Lingjuan Hong, Na Li, Victor Gasque, Sameet Mehta, Lupeng Ye, Yinyu Wu, Jinyu Li, Andreas Gewies, Jürgen Ruland, Karen K. Hirschi, Anne Eichmann, Caroline Hendry, David van Dijk, Arya Mani
Benchmarks for protective immunity from infection or severe disease after SARS-CoV-2 vaccination are still being defined. Here we characterized virus neutralizing and ELISA antibody levels, cellular immune responses, and viral variants in 4 separate groups: Healthy control participants weeks (early) or months (late) following vaccination in comparison to symptomatic SARS-CoV-2 infections after partial or full mRNA vaccination. During the study time, most symptomatic breakthrough infections were caused by the SARS-CoV-2 Alpha variant. Neutralizing antibody levels in the healthy controls were sustained over time against the vaccine parent virus, but decreased against the Alpha variant, whereas IgG titers and T cell responses against the parent virus and Alpha variant declined over time in healthy controls. Both partially and fully vaccinated patients with symptomatic infections had lower virus neutralizing antibody levels against parent virus than the healthy controls, similar IgG antibody titers and similar virus-specific T cell responses measured by IFN-γ. Compared to healthy controls, neutralization activity against the Alpha variant was lower in the partially vaccinated infected patients and tended toward lower in the fully vaccinated infected patients. In this cohort of breakthrough infections, parent virus neutralization was the superior predictor of breakthrough infections with the Alpha variant of SARS-CoV-2.
Han-Sol Park, Janna R. Shapiro, Ioannis Sitaras, Bezawit A. Woldemeskel, Caroline Garliss, Amanda Dziedzic, Jaiprasath Sachithanandham, Anne E. Jedlicka, Christopher A. Caputo, Kimberly E. Rousseau, Manjusha Thakar, San Suwanmanee, Pricila Hauk, Lateef Aliyu, Natalia I. Majewska, Sushmita Koley, Bela Patel, Patrick Broderick, Giselle Mosnaim, Sonya L. Heath, Emily S. Spivak, Aarthi Shenoy, Evan M. Bloch, Thomas J. Gniadek, Shmuel Shoham, Arturo Casadevall, Daniel Hanley, Andrea L. Cox, Oliver Laeyendecker, Michael Betenbaugh, Steven M. Cramer, Heba H. Mostafa, Andrew Pekosz, Joel N. Blankson, Sabra L. Klein, Aaron A.R. Tobian, David Sullivan, Kelly A. Gebo
TNF inhibitors are widely used to treat inflammatory diseases; however, 30-50% of treated patients develop new autoantibodies and 0.5-1% develop secondary autoimmune diseases, including lupus. TNF is required for formation of germinal centers (GCs), the site where high affinity autoantibodies are often made. We found that TNF deficiency in Sle1 mice induced TH17 T cells and enhanced the production of germline encoded, T-dependent IgG anti-cardiolipin antibodies but did not induce GC formation or precipitate clinical disease. We then asked whether a second hit could restore GC formation or induce pathogenic autoimmunity in TNF deficient mice. By using a range of immune stimuli, we found that somatically mutated autoantibodies and clinical disease can arise in the setting of TNF deficiency via extrafollicular pathways or via atypical GC-like pathways. This breach of tolerance may be due to defects in regulatory signals that modulate the negative selection of pathogenic autoreactive B cells.
Tam D. Quach, Weiqing Huang, Ranjit Sahu, Catherine M.M. Diadhiou, Chirag Raparia, Roshawn Johnson, Tung Ming Leung, Susan Malkiel, Peta-Gay Ricketts, Stefania Gallucci, Çagla Tükel, Chaim O. Jacob, Martin L. Lesser, Yong-Rui Zou, Anne Davidson
Systemic sclerosis (SSc) is a chronic multisystem orphan disease with a highly variable clinical course, significant mortality and a poorly understood complex pathogenesis. We identify an important role for a subpopulation of monocyte/macrophages characterized by surface expression of the scavenger receptor MARCO (MAcrophage Receptor with COllagenous structure) in chronic inflammation and fibrosis in SSc and in preclinical disease model. We show that MARCO+ monocytes and macrophages accumulate in lesional skin and lung in SSc patients and in the bleomycin-induced mouse model of SSc in topographic proximity to activated myofibroblasts. Short-term treatment of mice with a novel nanoparticle composed of a carboxylated FDA-approved biodegradable polymer, poly(lactic-co-glycolic) acid (PLG), which modulates activation and trafficking of MARCO+ inflammatory monocytes, markedly attenuated bleomycin-induced skin and lung inflammation and fibrosis. Mechanistically, in isolated cells in culture PLG nanoparticles inhibited TGF-β-dependent fibrotic responses in vitro. Thus MARCO+ monocytes are potent effector cells of skin and lung fibrosis, and can be therapeutically targeted in SSc using PLG nanoparticles.
Dan Xu, Swati Bhattacharyya, Wenxia Wang, Igal Ifergan, Ming-Yi Alice Chiang Wong, Daniele Procissi, Anjana Yeldandi, Swarna Bale, Roberta G. Marangoni, Craig Horbinski, Stephen D. Miller, John Varga
Alpha-1 antitrypsin (AAT) deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease, but the field lacks a large animal model that allows for longitudinal assessment of pulmonary function. We hypothesized that ferrets would model human AATD-related lung and hepatic disease. AAT-knockout (AAT-KO) and PiZZ (E342K, the most common mutation in humans) ferrets were generated and compared to matched controls using custom-designed flexiVent modules to perform pulmonary function tests (PFTs), quantitative computed tomography (QCT), bronchoalveolar lavage (BAL) proteomics, and alveolar morphometry. Complete loss of AAT (AAT-KO) led to increased pulmonary compliance and expiratory airflow limitation, consistent with obstructive lung disease. QCT and morphometry confirmed emphysema and airspace enlargement, respectively. Pathway analysis of BAL proteomics data revealed inflammatory lung disease and impaired cellular migration. The PiZ mutation resulted in altered AAT protein folding in the liver, hepatic injury, reduced plasma concentrations of AAT, and PiZZ ferrets developed obstructive lung disease. In summary, AAT-KO and PiZZ ferrets model the progressive obstructive pulmonary disease seen in AAT-deficient patients and may serve as a platform for preclinical testing of therapeutics including gene therapy.
Nan He, Xiaoming Liu, Amber R. Vegter, T. Idil A. Evans, Jaimie S. Gray, Junfeng Guo, Shashanna R. Moll, Lydia J. Guo, Meihui Luo, Ningxia Ma, Xingshen Sun, Bo Liang, Ziying Yan, Zehua Feng, Lisi Qi, Arnav S. Joshi, Weam Shahin, Yaling Yi, Katherine N. Gibson-Corley, Eric A. Hoffman, Kai Wang, Christian Mueller, John F. Engelhardt, Bradley H. Rosen
Subpial cortical demyelination is an important component of multiple sclerosis (MS) pathology contributing to disease progression, yet mechanism(s) underlying its development remain unclear. Compartmentalized inflammation involving the meninges may drive this type of injury. Given recent findings identifying substantial white matter (WM) lesion activity in patients with progressive MS, elucidating whether and how WM lesional activity relates to meningeal inflammation and subpial cortical injury is of interest. Using post-mortem formalin-fixed paraffin-embedded tissue blocks (range, 5-72 blocks; median, 30 blocks) for each of 27 progressive MS patients, we assessed the relationship between meningeal inflammation, the extent of subpial cortical demyelination, and the state of subcortical WM lesional activity. Meningeal accumulations of T cells and B cells, but not myeloid cells, were spatially adjacent to subpial cortical lesions and greater immune-cell accumulation was associated with higher subpial lesion numbers. Patients with a higher extent of meningeal inflammation harboured a greater proportion of active and mixed (active-inactive) WM lesions, and an overall lower proportion of inactive and remyelinated WM lesions. Our findings support the involvement of meningeal lymphocytes in subpial cortical injury, and also point to a potential link between inflammatory subpial cortical demyelination and pathological mechanisms occurring in the subcortical white matter.
Shanzeh M. Ahmed, Nina L. Fransen, Hanane Touil, Iliana Michailidou, Inge Huitinga, Jennifer L. Gommerman, Amit Bar-Or, Valeria Ramaglia
Type I interferons (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of antiretroviral therapy (ART)-treated HIV infection also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8 T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TI-IFN inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate pro-inflammatory plasma cytokines, expression of monocyte activation genes, IL-12 induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-β levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates (NHPs) treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrate that IFN-α blockade during ART-treated SIV infection is both safe and associated with the induction of immune/erythroid pathways that reduce viral persistence during ART while mitigating the weight loss and anemia that typically ensue following ART interruption.
Louise A. Swainson, Ashish Arunkumar Sharma, Khader Ghneim, Susan Pereira Ribeiro, Peter Wilkinson, Richard M. Dunham, Rebecca G. Albright, Samson Wong, Jacob D. Estes, Michael Piatak, Steven G. Deeks, Peter W. Hunt, Rafick-Pierre Sekaly, Joseph M. McCune
No posts were found with this tag.