Pulmonology
Abstract
Viral lower respiratory tract infections are common early in life and are associated with long-term development of asthma, a chronic condition defined by reversible airflow obstruction secondary to inflammation. Understanding the immunologic mechanism connecting these two pathologies observed early in life becomes imperative to guide therapeutic measures. To investigate this connection, neonatal (day of life 4-6) or adult mice were infected with human metapneumovirus (HMPV) followed by a secondary HMPV infection 6 weeks later. Mice initially infected as neonates demonstrate increased mucus production, eosinophil recruitment, airway hyperresponsiveness, and Th2 T-cell differentiation following re-challenge compared to adult mice rechallenged with HMPV. Neonatal HMPV infection led to formation of Th2 clonally expanded tissue resident memory (TRM) T cells that were absent after adult HMPV. FTY720-mediated disruption of lymphocyte circulation demonstrated TRMs contribute to pathology. Local depletion of lung CD4+ T cells and JAK2-inhibition mitigated pathology. These findings suggest TRMs uniquely generated after early life viral infection can contribute to Th2-driven asthma pathology.
Authors
Emma E. Brown, Jie Lan, Olivia B. Parks, Li Fan, Dequan Lou, Alysia McCray, Lisa Mathews, Alexander J. Wardropper, Anna Shull, Michelle L. Manni, Hēth R. Turnquist, Kong Chen, Taylor Eddens
Abstract
Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.
Authors
Adam S. Krebs, Tomi Lazarov, Anthony T. Reynolds, Kimberly A. Dill-McFarland, Abigail Xie, James M. Bean, Muxue Du, Olivier Levy, John A. Buglino, Aaron Zhong, Anna-Lena Neehus, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Elouise E. Kroon, Marlo Möller, Thomas R. Hawn, Ting Zhou, Lydia W.S. Finley, Marc Antoine Jean Juste, Dan W. Fitzgerald, Frederic Geissmann, Michael S. Glickman
Abstract
Aberrant neutrophil (PMN) accumulation in the tissue induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and 'do not eat me' signals due to impaired synthesis of the deubiquitinase, A20. Decreased A20 levels, in turn, activated the transcription factor NFκB and the secretion of MIP2α (human homolog of IL8) in ECs. EC-secreted MIP2α/IL8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in EC or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg–/– mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC-Erg-A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN-CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.
Authors
Vigneshwaran Vellingiri, Vijay Avin Balaji Ragunathrao, Jagdish Chandra Joshi, Md Zahid Akhter, Mumtaz Anwar, Somenath Banerjee, Sayanti Datta, Viktor Pinneker, Steven M. Dudek, Yoshikazu Tsukasaki, Sandra Pinho, Dolly Mehta
Abstract
Alveolar macrophages (AMs) catabolize lipid-rich pulmonary surfactant to support gas exchange and have anti-inflammatory programming to limit tissue damage in response to minor challenges. GATA transcription factors (TFs) shape immune cell fates and GATA2 is expressed in a lung-specific manner in macrophages. GATA2 mutations and lung macrophage downregulation of GATA2 have been associated with chronic pulmonary pathologies in humans, but the role of GATA2 in coordinating AM function is not well defined. Using mice with myeloid-specific deletion of the GATA2 DNA binding C-terminal zinc finger domain, we show that GATA2 deficiency promotes enhanced inflammatory gene expression and metabolic dysfunction in AMs in response to type 2 stimuli. While homeostatic functions of AMs remain largely intact, GATA2 deficiency increases expression of type 2 response genes during IL-33-induced inflammation. Coincident with GATA2-dependent expression of genes in metabolic pathways, seahorse metabolic flux analysis indicates that AM metabolism is compromised in the absence of GATA2. AM GATA2-dependent gene networks are enriched for targets of TFs previously demonstrated to interact with GATA2 in other cellular contexts, including PU.1, PPARγ, and other regulators of AM function. Our data suggest that GATA2 modulates AM metabolic and transcriptomic programming to restrain responses and maintain AM identity during inflammation.
Authors
Morgan Jackson-Strong, Satarupa Ganguly, Aaron Francis, Flavia Rago, Jitendra Kanshana, Brandon A. Michalides, Lihong Teng, Omkar S. Betsur, Sonia Kruszelnicki, Karsen E. Shoger, Aaron Kim, Kay Bajpai, Amina Suleyman, Abigail Sekyere, Mika Hara, Varsha Sriram, Alok Kumar, Greg M. Delgoffe, Niranjana Natarajan, John F. Alcorn, Alison B. Kohan, Rachel A. Gottschalk
Abstract
BACKGROUND. To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. METHODS. PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic white participants (n=6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n=2,466), ECLIPSE (n=1,858), MassGeneral Brigham Biobank (n=15,152), and All of Us (n=118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n=5,173) and UK Biobank (n=5,012). RESULTS. PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include RAGE/sRAGE, IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. CONCLUSIONS. Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. TRIAL REGISTRATION. COPDGene: NCT00608764; ECLIPSE: NCT00292552.
Authors
Chengyue Zhang, Iain R. Konigsberg, Yixuan He, Jingzhou Zhang, Tinashe Chikowore, William B. Feldman, Xiaowei Hu, Yi Ding, Bogdan Pasaniuc, Diana Chang, Qingwen Chen, Jessica A. Lasky-Su, Julian Hecker, Martin D. Tobin, Jing Chen, Sean Kalra, Katherine A. Pratte, Hae Kyung Im, Emily S. Wan, Ani Manichaikul, Edwin K. Silverman, Russell P. Bowler, Leslie A. Lange, Victor E. Ortega, Alicia R. Martin, Michael H. Cho, Matthew R. Moll
Abstract
Systemic sclerosis (SSc) is a complex and heterogeneous condition characterized by progressive fibrosis in multiple organs. Recent studies implicate plasminogen activator inhibitor 1 (PAI-1) in the pathogenesis of SSc, and PAI-1 is considered as a potential target for therapy. Here, using single-cell and spatial RNA-seq analysis of skin biopsies from 18 healthy individuals and 22 SSc patients, we found elevated PAI-1 co-localizing to myofibroblasts with enriched extracellular matrix-associated biological processes. Treatment of SSc dermal fibroblasts with the small molecule PAI-1 inhibitor MDI-2517 reduced the expression of the profibrotic markers COL1A1 and ACTA2. To investigate the therapeutic potential of MDI-2517, we evaluated its efficacy in reducing fibrosis in a preclinical model of SSc. Treatment of mice with MDI-2517 significantly reduced both skin and lung fibrosis and was superior to treatment with either pirfenidone or mycophenolate mofetil. Additionally, MDI-2517 attenuated weight loss and significantly reduced the expression of key profibrotic markers. Compared to tiplaxtinin, another PAI-1 inhibitor previously shown to be effective in a model of SSc, MDI-2517 was found to have superior efficacy at a 10-fold lower dose. These findings highlight the role of PAI-1 in the pathogenesis of SSc, and the potential of MDI-2517 for the treatment of SSc.
Authors
Enming J. Su, Pei-Suen Tsou, Mark Warnock, Natalya Subbotina, Kris Mann, Sirapa Vichaikul, Alyssa Rosek, Lisa Leung, Xianying Xing, Enze Xing, Olesya Plazyo, Rachael Bogle, Lam C. Tsoi, Cory D. Emal, Dinesh Khanna, John Varga, Thomas H. Sisson, Johann E. Gudjonsson, Daniel A. Lawrence
Abstract
Lung development relies on diverse cell intrinsic and extrinsic mechanisms to ensure proper cellular differentiation and compartmentalization. In addition, it requires precise integration of multiple signaling pathways to temporally regulate morphogenesis and appropriate cell specification. To accomplish this, organogenesis relies on epigenetic and transcriptional regulators to promote cell fate and inhibit alternative cell fates. Using genetic mouse and human embryonic stem cell (hESC) differentiation models, tissue explants, and single-cell transcriptomic analysis, we demonstrated that Bromodomain Containing Protein 4 (BRD4) is required for mammalian lung morphogenesis and cell fate. Endodermal deletion of BRD4 impaired epithelial-mesenchymal crosstalk, leading to disrupted proximal-distal patterning and branching morphogenesis. Moreover, temporal deletion of BRD4 revealed developmental stage-specific defects in airway and alveolar epithelial cell specification with a predominant role in proximal airway cell fate. Similarly, BRD4 promoted lung endodermal cell differentiation into airway lineages in a hESC-derived lung organoid model. Together, these data demonstrated that BRD4 orchestrates early lung morphogenesis and separately regulates cell specification, indicating a multifunctional and evolutionarily conserved role for BRD4 in mammalian lung development.
Authors
Hongbo Wen, Derek C. Liberti, Prashant Chandrasekaran, Shahana Parveen, Kwaku K. Quansah, Mijeong Kim, Ana N. Lange, Abigail T. Marquis, Sylvia N. Michki, Annabelle Jin, MinQi Lu, Ayomikun A. Fasan, Sriyaa Suresh, Shawyon P. Shirazi, Lisa R. Young, Jennifer M.S. Sucre, Maria C. Basil, Rajan Jain, David B. Frank
Abstract
BACKGROUND After identifying 2 immunomarkers of acute injury, KIM-1 and LCN2, in all kidney biopsies from 31 patients with COVID-19 pneumonia and de novo kidney dysfunction, we investigated whether circulating markers of kidney epithelial injury are common in patients with laboratory-confirmed COVID-19 who require oxygen support but do not have critical illness.METHODS We studied 196 patients admitted to 15 hospitals with moderate to severe pneumonia who were enrolled in 2 independent randomized clinical trials. We measured 41 immune mediators and markers of kidney and endothelial injury in peripheral blood in these patients within 24 hours of randomization.RESULTS We constructed a generalized linear CORIMUNO model combining serum levels of KIM-1, LCN2, IL-10, and age at hospital admission that showed high discrimination for mortality (derivation cohort: AUC = 0.82, 95% CI: 0.73–0.92; validation cohort: AUC = 0.83, 95% CI: 0.74–0.92). An early rise in circulating kidney injury markers, in the absence of acute kidney injury criteria, was markedly associated with the risk of developing a severe form of COVID-19 and death within 3 months.CONCLUSION The CORIMUNO score may be a helpful tool for risk stratification, and for the first time to our knowledge, it identifies the overlooked impact of subclinical kidney injury on pneumonia outcomes.TRIAL REGISTRATION ClinicalTrials.gov NCT04324047, NCT04324073, and NCT04331808.FUNDING This research was funded by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC COVID-19–20–0151, PHRC COVID-19–20–0029), Fondation de l’Assistance Publique Hôpitaux de Paris (Alliance Tous Unis Contre le Virus), Assistance Publique Hôpitaux de Paris, and grants from the Fondation pour la Recherche Médicale (FRM) (REA202010012514) and Agence Nationale de Recherches sur le Sida and emerging infectious diseases (ANRS) (ANRS0147) from the VINTED sponsorship.
Authors
Olivia Lenoir, Florence Morin, Anouk Walter-Petrich, Léa Resmini, Mohamad Zaidan, Nassim Mahtal, Sophie Ferlicot, Victor G. Puelles, Nicola Wanner, Julien Dang, Thibaut d’Izarny-Gargas, Jana Biermann, Benjamin Izar, Stéphanie Baron, Benjamin Terrier, Ziad A. Massy, Marie Essig, Aymeric Couturier, Olivia May, Xavier Belenfant, David Buob, Isabelle Brocheriou, Hassan Izzedine, Yannis Lombardi, Hélène François, Anissa Moktefi, Vincent Audard, Aurélie Sannier, Eric Daugas, Matthieu Jamme, Guylaine Henry, Isabelle Le Monnier de Gouville, Catherine Marie, Laurence Homyrda, Céline Verstuyft, Sarah Tubiana, Ouifiya Kafif, Valentine Piquard, Maxime Dougados, Tobias B. Huber, Marine Livrozet, Jean-Sébastien Hulot, Cedric Laouénan, Jade Ghosn, France Mentré, Alexandre Karras, Yazdan Yazdanpanah, Raphaël Porcher, Philippe Ravaud, Sophie Caillat-Zucman, Xavier Mariette, Olivier Hermine, Matthieu Resche-Rigon, Pierre-Louis Tharaux, CORIMUNO-19 collaborative group
Abstract
BACKGROUND. Idiopathic pulmonary arterial hypertension (IPAH) alters right ventricular size and function, curtailing life-expectancy. Patients may experience angina and myocardial ischemia. However, the mechanisms underlying these changes are poorly understood. METHODS. A cross-sectional, case-control design of coronary pathophysiology (in vivo and ex vivo) in IPAH. Patients with IPAH (Group-1.1) undergoing clinically indicated right heart catheterization were prospectively enrolled. Participants underwent functional testing during coronary angiography using a dual pressure/temperature-sensitive guidewire. Cardiovascular magnetic resonance measured left and right ventricular mass and function. Autopsy cardiac tissues from end-stage PAH (Group-1) and control individuals were analyzed for right ventricular pathophysiology. RESULTS. Eleven participants with IPAH and 15 control participants completed the protocol (IPAH: 45±15 years, 73% female; controls: 58.3±9.1 years, 73% female). 73% (n=8) of IPAH patients had an elevated index of microcirculatory resistance (IMR >25) and 55% (n=6) had reduced coronary flow reserve (CRF <2.0). The mean IMR was significantly higher in IPAH participants (39.2±27.0 vs. 15.3±5.0, p=0.002) whereas mean CFR was lower (2.8±2.1 vs. 4.0±1.4; p=0.077). Paired right coronary artery/ventricular measurements (n=6) revealed IMR positively correlated with right ventricular mass (r=0.91, p=0.12), and negatively with CFR (r=-0.82, p=0.046). Compared to controls (n=5), PAH participants (n=4) had reduced right ventricular capillary density (111±18 vs. 167±20, p=0.032), increased cardiomyocyte area (383±118μm2 vs. 231±61μm2, p=0.0390), and increased mural area in small pre-capillary arterioles (127±10μm2 vs. 107±20μm2, p=0.041). CONCLUSIONS. Coronary microvascular dysfunction is prevalent in IPAH and correlates with increased right ventricular mass. Histopathology revealed vascular rarefaction and remodeling of pre-capillary arterioles. The clinical significance merits prospective evaluation. Invasive coronary function testing was feasible and safe in IPAH, providing a platform to assess therapeutic impacts on cardiac microvascular function.
Authors
Erin Boland, Michael G. Freeman, David S. Corcoran, Thomas J. Ford, Barry Hennigan, Damien Collison, Aida Llucià-Valldeperas, Frances S. de Man, Kanarath P. Balachandran, Martin Johnson, Colin Church, Colin Berry
Abstract
Activation of lung fibroblasts in response to epithelial injury and inflammation provokes pulmonary fibrosis (PF). Endogenous molecular brakes counteracting fibroblast activity can be targets for therapies. Preclinical studies of synthetic C-type natriuretic peptide (CNP) indicated that this hormone might provide such a brake. As shown here, CNP exerts antifibrotic effects in cultured lung fibroblasts as well as precision cut lung slices from patients with PF, supporting clinical relevance. Therefore, augmenting or supplementing endogenous CNP could improve the treatment of such patients. To unravel whether paracrine CNP counteracts inflammation-driven PF, we studied mice with fibroblast-restricted knock-out of guanylyl-cyclase-B (GC-B), its cGMP-synthesizing receptor. Fibroblast GC-B-KO mice had enhanced bleomycin-induced lung inflammation, with increased expression of proinflammatory, profibrotic cytokines. Nevertheless, subsequent PF was not exacerbated. Molecular studies revealed that inflammation led to inhibition of CNP signaling in resident myofibroblasts, namely GC-B downregulation and induction of CNP/cGMP-degrading pathways. Despite this, a single subcutaneous injection of the recently developed long-acting CNP analog, MS~[Gln6,14]CNP-38, abrogated experimental lung inflammation and fibrosis. We conclude that CNP signaling in lung fibroblasts has anti-inflammatory and antifibrotic effects. Attenuation of this endogenous brake participates in the pathogenesis of PF and rescuing this pathway with long-acting CNP-analogs may have therapeutic potential.
Authors
Rene Weyer, Katharina Völker, Tamara Potapenko, Lisa Krebes, Marco Abesser, Anna-Lena Friedrich, Eva Lessmann, Ali Khadim, Clemens Ruppert, Elie El Agha, Dalia Sheta, Andreas Beilhack, Daniel V. Santi, Eric L. Schneider, Michaela Kuhn, Swati Dabral
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