Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation

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Abstract

A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of mortality after lung transplantation (LTx), is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early post-lung transplantation to form the C3 convertase, a critical enzyme that cleaves the central complement component C3. We hypothesized that LTx recipients with a genetic predisposition to enhanced complement activation have worse CLAD-free survival mediated through increased adaptive alloimmunity. We interrogated a known functional C3 polymorphism (C3R102G) that increases complement activation through impaired C3 convertase inactivation in two independent LTx recipient cohorts. C3R102G, identified in at least one out of three LTx recipients, was associated with worse CLAD-free survival, particularly in the subset of recipients who developed donor-specific antibodies (DSAs). In a mouse orthotopic lung transplant model, impaired recipient complement regulation led to B cell-dependent CLAD pathology despite moderate differences in graft-infiltrating effector T cells. Dysregulated complement regulation promoted intragraft accumulation of memory B cells and antibody-secreting cells, leading to increased local and circulating DSA levels in mice. In summary, genetic predisposition to complement activation is associated with an increased humoral response and worse CLAD-free survival.

Authors

Hrishikesh S. Kulkarni, Laneshia K. Tague, Daniel R. Calabrese, Fuyi Liao, Zhiyi Liu, Lorena Garnica, Nishanth R. Shankar, Xiaobo Wu, Devesha H. Kulkarni, Aayusha Thapa, Dequan Zhou, Yan Tao, Victoria E. Davis, Cory T. Bernadt, Derek E. Byers, Catherine Chen, Howard J. Huang, Chad A. Witt, Ramsey R. Hachem, Daniel Kreisel, John P. Atkinson, John R. Greenland, Andrew E. Gelman

Neutrophil to lymphocyte ratio varies in magnitude and biomarker utility based on patient demographics

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Abstract

Authors

William Ang, Travis D. Kerr, Ananya Kodiboyena, Cristina Valero, Joris L. Vos, Vladimir Makarov, Alex A. Adjei, Luc G.T. Morris, Stephanie L. Schmit, Natalie L. Silver, Sujata Patil, Daniel J. McGrail

Lamin A/C regulates lipid metabolism and inflammation: insights from models of familial partial lipodystrophy 2

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Abstract

Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by adipose tissue loss and redistribution, and metabolic dysfunction. FPLD2 is caused by pathogenic variants in the LMNA gene, encoding nuclear lamins A/C, structural proteins that control nuclear function and gene expression. However, the mechanisms driving adipocyte loss in FPLD2 remain poorly defined. In this study, we recruited eight families with developing or established FPLD2 and performed clinical, histological, and transcriptomic analyses of subcutaneous adipose tissue biopsies. Bulk and single-nuclei RNA-sequencing revealed suppression of lipid metabolism and mitochondrial pathways, alongside increased inflammation. These signatures were mirrored in tamoxifen-inducible adipocyte-specific Lmna knockout mice, in which lamin A/C-deficient adipocytes shrank and disappeared. Lmna-deficient fibroblasts shared similar gene expression changes, linked to altered chromatin accessibility, underscoring lamin A/C’s potential regulatory role in lipid metabolism and inflammatory programs. By directly comparing atrophic and hypertrophic adipose depots in FPLD2, and integrating human, mouse, and in vitro models, this study provides new insights into disease progression and potential therapeutic targets.

Authors

Jessica N. Maung, Rebecca L. Schill, Akira Nishii, Maria Foss de Freitas, Bonje N. Obua, Marcus Nygård, Maria D. Mendez-Casillas, Isabel D.K. Hermsmeyer, Donatella Gilio, Ozge Besci, Yang Chen, Brian Desrosiers, Rose E. Adler, Anabela D. Gomes, Merve Celik Guler, Hiroyuki Mori, Romina M. Uranga, Ziru Li, Hadla Hariri, Liping Zhang, Anderson de Paula Souza, Keegan S. Hoose, Kenneth T. Lewis, Taryn A. Hetrick, Paul Cederna, Carey N. Lumeng, Susanne Mandrup, Elif A. Oral, Ormond A. MacDougald

Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in mice

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Demyelination associated microglia (DMAM) orchestrate the regenerative response to demyelination by clearing myelin debris and promoting oligodendrocyte maturation. Peroxisomal metabolism has emerged as a candidate regulator of DMAMs, though the cell-intrinsic contribution in microglia remains undefined. Here we elucidate the role of peroxisome integrity in DMAMs using cuprizone mediated demyelination coupled with conditional knockout of peroxisome biogenesis factor 5 (PEX5) in microglia. Absent demyelination, PEX5 conditional knockout (PEX5cKO) had minimal impact on homeostatic microglia. However, during cuprizone-induced demyelination, the emergence of DMAMs unmasked a critical requirement for peroxisome integrity. At peak demyelination, PEX5cKO DMAMs exhibited increased lipid droplet burden and reduced lipophagy suggestive of impaired lipid catabolism. Although lipid droplet burden declined during the remyelination phase, PEX5cKO DMAMs accumulated intralysosomal crystals and curvilinear profiles, which features were largely absent in controls. Aberrant lipid processing was accompanied by elevated lysosomal damage markers and downregulation of the lipid exporter gene Apoe, consistent with defective lipid clearance. Furthermore, the disruptions in PEX5cKO DMAMs were associated with defective myelin debris clearance and impaired remyelination. Together, these findings delineate a stage-specific role for peroxisomes in coordinating lipid processing pathways essential to DMAM function and necessary for enabling a pro-remyelinating environment.

Authors

Joseph A. Barnes-Vélez, Xiaohong Zhang, Yaren L. Peña Señeriz, Kiersten A. Scott, Yinglu Guan, Jian Hu

Early brain-wide disruption of sleep microarchitecture in Amyotrophic Lateral Sclerosis

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BACKGROUND. Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, is preceded by an early period unrelated to motor symptoms, including altered sleep, with increased wakefulness and decreased deep NREM. Whether these alterations in sleep macroarchitecture are associated with, or even precede abnormalities in sleep-related EEG features remains unknown. METHODS. Here, we characterised sleep microarchitecture using polysomnography in patients with ALS (n=33) and controls (n=32), and in asymptomatic carriers of SOD1 or C9ORF72 mutations (n=57) and non-carrier controls (n=30). Patients and controls with factors that could confound sleep structure, including respiratory insufficiency, were prospectively excluded. Results were complemented in three ALS mouse models (Sod1G86R , Fus∆NLS/+ and TDP-43Q331K ). RESULTS. We observed a brain-wide reduction in the density of sleep spindles, slow oscillations and K-complexes in both early-stage ALS patients and presymptomatic gene carriers. These defects in sleep spindles and slow oscillations correlate with cognitive performance in both cohorts, particularly with scores on memory, verbal fluency and language function. Alterations in sleep microarchitecture were replicated in three mouse models and decreases in sleep spindles were rescued following intracerebroventricular supplementation of MCH or by the oral administration of a dual orexin receptor antagonist. CONCLUSION. Sleep microarchitecture is associated with cognitive deficits and is causally linked to aberrant MCH and orexin signalling in ALS. FUNDING. This work was funded by Agence Nationale de la Recherche (ANR-24-CE37-4064, ANR-10-IDEX-0002, ANR-20-SFRI-0012), Fondation Thierry Latran, Association Francaise de Recherche sur la sclérose latérale amyotrophique, Association Française contre les Myopathies (#28944), TargetALS and JPND.

Authors

Christina Lang, Simon J. Guillot, Dorothee Lule, Luisa T. Balz, Antje Knehr, Patrick Weydt, Johannes Dorst, Katharina Kandler, Hans-Peter Müller, Jan Kassubek, Laura Wassermann, Sandrine Da Cruz, Francesco Roselli, Albert C. Ludolph, Matei Bolborea, Luc Dupuis

A missense mutation in Muc2 promotes gut microbiome- and metabolome-dependent colitis-associated tumorigenesis

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Colitis-associated cancer (CAC) arises from a complex interplay between host and environmental factors. In this report, we investigated the role of the gut microbiome using Winnie mice, a UC-like model with a missense mutation in the Muc2 gene. Upon rederivation from a conventional (CONV) to a specific-pathogen-free (SPF) facility, Winnie mice developed severe colitis and, notably, spontaneous CAC that progressively worsened over time. In contrast, CONV Winnie showed only mild colitis but no tumorigenesis. By comparison, when rederived into germ-free (GF) conditions, SPF Winnie mice were protected from colitis and colon tumors, indicating an essential role for the gut microbiome in the development of CAC in these mice. Using shotgun metagenomics, metabolomics, and lipidomics, we identified a distinct pro-inflammatory microbial and metabolic signature that potentially drives the transition from colitis to CAC. Fecal microbiota transplantation (FMT), using either SPF Winnie or WT (Bl/6) donors into GF Winnie recipients, demonstrated that while colitis developed regardless of the donor, only FMT from SPF Winnie donors resulted in CAC. Our studies present a relevant model of CAC, providing strong evidence that the microbiome plays a key role in its pathogenesis, thereby challenging the concept of colon cancer as a strictly non-transmissible disease.

Authors

Giulio Verna, Stefania De Santis, Bianca N. Islam, Eduardo M. Sommella, Danilo Licastro, Liangliang Zhang, Fabiano De Almelda Celio, Emily N. Miller, Fabrizio Merciai, Vicky Caponigro, Wei Xin, Pietro Campiglia, Theresa T. Pizarro, Marcello Chieppa, Fabio Cominelli

Selective inhibition of long isoforms of phosphodiesterase 4D mitigates liver fibrosis in mouse models

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Chronic inflammation leads to tissue fibrosis which can disrupt the function of the parenchyma of the organ and ultimately lead to organ failure. The most prevalent form of this occurs in chronic hepatitis which leads to liver fibrosis and, ultimately, cirrhosis and hepatic failure. Although there is no specific treatment for fibrosis, the phosphodiesterase 4 (PDE4) competitive inhibitors have been shown to ameliorate fibrosis in rodent models. However, competitive inhibitors of PDE4 have shown significantly reduced effectiveness due to severe gastrointestinal side effects. The PDE4 family is composed of four genes (PDE4A–D) with each having up to 9 differentially spliced isoforms. Here, we report that PDE4D expression is specifically elevated during the hepatic fibrosis stage of liver disease progression. Furthermore, the expression of the long isoforms of PDE4D is selectively elevated in activated hepatic stellate cells, leading to the enhanced accumulation of extracellular matrix components. In a mouse model of liver fibrosis, genetic ablation of PDE4D or pharmacological inhibition using D159687, a selective allosteric inhibitor targeting the long isoforms of PDE4D, suppresses the expression of inflammatory and profibrogenic genes. These findings establish the long isoforms of PDE4D as key drivers of liver fibrosis and highlight their potential as therapeutic targets to ameliorate liver fibrosis.

Authors

Jeonghan Kim, Heeeun Yoon, Seoung Chan Joe, Antoine Smith, Jinsung Park, Geunhye Hong, Ji Myeong Ha, Eun Bae Kim, Ekihiro Seki, Myung K. Kim, Hae-Ock Lee, Ho-Shik Kim, Jay H. Chung

Identification of serum protein biomarkers for clear cell renal cell carcinoma using patient-derived xenografts

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Authors

Dalin Zhang, Chun-Lung Chiu, Fernando Jose Garcia Marques, Abel Bermudez, Christian R. Hoerner, Nicholas Hadi, Elise Wang, Thomas J. Metzner, Ludimila Trabanino, John T. Leppert, Hongjuan Zhao, Robert Tibshirani, Alice C. Fan, Sharon J. Pitteri, James D. Brooks

Human adenosine deaminase type 2 deficiency: enhanced NK cell activation but impaired maturation and function

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Authors

Jarne Beliën, Amber De Visscher, Bethany Pillay, Marjon Wouters, Verena Kienapfel, Eline Bernaerts, Tania Mitera, Nele Berghmans, Bénédicte Dubois, Leen Moens, Patrick Matthys, Isabelle Meyts

A recurrent ACAA2 variant causes a dominant syndrome of lipodystrophy, lipomatosis, infantile steatohepatitis and hypoglycemia

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Authors

Vinaya Simha, Mary Kate LoPiccolo, Anna Platt, Rebecca J. Brown, Xandria Johnson, Deanna Alexis Carere, Colleen Donnelly, Matthew T. Snyder, Chao Xing, Thomas P. Mathews, Purva Gopal, Stephen C. Ward, Diana R. Tomchick, Anil K. Agarwal, Ralph J. DeBerardinis, Abhimanyu Garg