-
The Journal of Clinical Investigation Oct 2020Epithelial cell dysfunction has emerged as a central component of the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF).... (Review)
Review
Epithelial cell dysfunction has emerged as a central component of the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF). Alveolar type 2 (AT2) cells represent a metabolically active lung cell population important for surfactant biosynthesis and alveolar homeostasis. AT2 cells and other distal lung epithelia, like all eukaryotic cells, contain an elegant quality control network to respond to intrinsic metabolic and biosynthetic challenges imparted by mutant protein conformers, dysfunctional subcellular organelles, and dysregulated telomeres. Failed AT2 quality control components (the ubiquitin-proteasome system, unfolded protein response, macroautophagy, mitophagy, and telomere maintenance) result in diverse cellular endophenotypes and molecular signatures including ER stress, defective autophagy, mitochondrial dysfunction, apoptosis, inflammatory cell recruitment, profibrotic signaling, and altered progenitor function that ultimately converge to drive downstream fibrotic remodeling in the IPF lung. As this complex network becomes increasingly better understood, opportunities will emerge to identify targets and therapeutic strategies for IPF.
Topics: Alveolar Epithelial Cells; Animals; Autophagy; Cell Lineage; Humans; Idiopathic Pulmonary Fibrosis; Mitophagy; Models, Biological; Mutation; Proteasome Endopeptidase Complex; Proteostasis; Pulmonary Surfactant-Associated Protein C; Signal Transduction; Telomere Homeostasis; Ubiquitin; Unfolded Protein Response
PubMed: 32870817
DOI: 10.1172/JCI139519 -
International Journal of Molecular... Feb 2020Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important... (Review)
Review
Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important factor in CNS water and potassium homeostasis. Changes in AQP4 activity and expression have been implicated in several CNS disorders, including (but not limited to) epilepsy, edema, stroke, and glioblastoma. For this reason, many studies have been done to understand the various ways in which AQP4 is regulated endogenously, and could be regulated pharmaceutically. In particular, four regulatory methods have been thoroughly studied; regulation of gene expression via microRNAs, regulation of AQP4 channel gating/trafficking via phosphorylation, regulation of water permeability using heavy metal ions, and regulation of water permeability using small molecule inhibitors. A major challenge when studying AQP4 regulation is inter-method variability. A compound or phosphorylation which shows an inhibitory effect in vitro may show no effect in a different in vitro method, or even show an increase in AQP4 expression in vivo. Although a large amount of variability exists between in vitro methods, some microRNAs, heavy metal ions, and two small molecule inhibitors, acetazolamide and TGN-020, have shown promise in the field of AQP4 regulation.
Topics: Acetazolamide; Animals; Aquaporin 4; Central Nervous System; Central Nervous System Diseases; Homeostasis; Humans; Ions; Metals; MicroRNAs; Niacinamide; Permeability; Phosphorylation; Potassium; Proteolipids; Thiadiazoles; Water
PubMed: 32111087
DOI: 10.3390/ijms21051603 -
The Journal of Clinical Investigation Oct 2023B cell clonal expansion and cerebrospinal fluid (CSF) oligoclonal IgG bands are established features of the immune response in multiple sclerosis (MS). Clone-specific...
B cell clonal expansion and cerebrospinal fluid (CSF) oligoclonal IgG bands are established features of the immune response in multiple sclerosis (MS). Clone-specific recombinant monoclonal IgG1 Abs (rAbs) derived from MS patient CSF plasmablasts bound to conformational proteolipid protein 1 (PLP1) membrane complexes and, when injected into mouse brain with human complement, recapitulated histologic features of MS pathology: oligodendrocyte cell loss, complement deposition, and CD68+ phagocyte infiltration. Conformational PLP1 membrane epitopes were complex and governed by the local cholesterol and glycolipid microenvironment. Abs against conformational PLP1 membrane complexes targeted multiple surface epitopes, were enriched within the CSF compartment, and were detected in most MS patients, but not in inflammatory and noninflammatory neurologic controls. CSF PLP1 complex Abs provide a pathogenic autoantibody biomarker specific for MS.
Topics: Mice; Animals; Humans; Multiple Sclerosis; Myelin Sheath; Immunoglobulin G; Epitopes; Proteolipids
PubMed: 37561592
DOI: 10.1172/JCI162731 -
The Journal of Pediatrics Dec 2020
Topics: Biological Products; Double-Blind Method; Humans; Infant, Newborn; Peptide Fragments; Phosphatidylcholines; Phospholipids; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Protein C; Respiratory Distress Syndrome, Newborn; Surface-Active Agents
PubMed: 32818480
DOI: 10.1016/j.jpeds.2020.08.030 -
The Journal of Clinical Investigation Jan 2021Immune evasion is a pivotal event in tumor progression. To eliminate human cancer cells, current immune checkpoint therapy is set to boost CD8+ T cell-mediated...
Immune evasion is a pivotal event in tumor progression. To eliminate human cancer cells, current immune checkpoint therapy is set to boost CD8+ T cell-mediated cytotoxicity. However, this action is eventually dependent on the efficient recognition of tumor-specific antigens via T cell receptors. One primary mechanism by which tumor cells evade immune surveillance is to downregulate their antigen presentation. Little progress has been made toward harnessing potential therapeutic targets for enhancing antigen presentation on the tumor cell. Here, we identified MAL2 as a key player that determines the turnover of the antigen-loaded MHC-I complex and reduces the antigen presentation on tumor cells. MAL2 promotes the endocytosis of tumor antigens via direct interaction with the MHC-I complex and endosome-associated RAB proteins. In preclinical models, depletion of MAL2 in breast tumor cells profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth, suggesting that MAL2 is a potential therapeutic target for breast cancer immunotherapy.
Topics: Animals; Antigen Presentation; Antigens, Neoplasm; Breast Neoplasms; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Female; Histocompatibility Antigens Class I; Humans; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Inbred BALB C; Mice, Nude; Myelin and Lymphocyte-Associated Proteolipid Proteins; Neoplasm Proteins; Tumor Escape
PubMed: 32990678
DOI: 10.1172/JCI140837 -
Cell Reports Aug 2021Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic...
Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPC). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPC-expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception.
Topics: Alveolar Epithelial Cells; Animals; Cell Line; Cell Proliferation; Energy Metabolism; Genetic Predisposition to Disease; Humans; Induced Pluripotent Stem Cells; Inflammation Mediators; Lung Diseases, Interstitial; Mice, Knockout; Mutation; NF-kappa B; Phenotype; Proteostasis; Pulmonary Surfactant-Associated Protein C; Signal Transduction; Mice
PubMed: 34469722
DOI: 10.1016/j.celrep.2021.109636 -
Methods in Molecular Biology (Clifton,... 2021Experimental autoimmune encephalomyelitis, originally experimental allergic encephalomyelitis, is the well-known animal model of multiple sclerosis, an immune- mediated,...
Experimental autoimmune encephalomyelitis, originally experimental allergic encephalomyelitis, is the well-known animal model of multiple sclerosis, an immune- mediated, demyelinating, inflammatory chronic disease of the central nervous system. The experimental disease is widely utilized to test new therapies in preclinical studies, to investigate new hypothesis on the possible pathogenic mechanisms of autoimmune reaction directed against the central nervous system or more generally to investigate the interactions between the immune system and the central nervous system that lead to neuroinflammation. The experimental autoimmune encephalomyelitis may be induced following different protocols in mammals, including nonhuman primates, and autoreactive CD4+ T-lymphocytes directed against myelin antigens are the main factors. Here, after introducing the model, we describe the protocol to induce active EAE in inbred mice, we report on a table the different clinical courses of EAE depending on the combination of antigen /mouse strain and we provide indications on how to evaluate the clinics and pathology of this induced disease.
Topics: Animals; Antigens; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Lipids; Male; Mice, Inbred Strains; Mycobacterium tuberculosis; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Phenotype; Research Design; Sex Factors; Species Specificity; T-Lymphocytes; Workflow; Mice
PubMed: 33928565
DOI: 10.1007/978-1-0716-1311-5_27