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This Month in AJP

    Open ArchivePublished:December 10, 2018DOI:https://doi.org/10.1016/j.ajpath.2018.12.001

        Understanding Visual Impairment in Farber Disease

        The full effects of acid ceramidase (ACDase) deficiency—resulting from mutations in the ASAH1 gene, which may cause Farber disease—on vision are poorly understood. Using a previously generated mouse model of Farber disease, Yu et al (Am J Pathol 2019, 189:320–338) studied retinal and ocular pathology resulting from mutations in acid ceramidase. Mice with a mutant human ASAH1 ortholog exhibited progressive retinal and optic nerve pathology and inflammation, retinal dysplasia, and significant accumulation of ceramides and other sphingolipids in retinal tissues. These mice also showed decreased retinal and visual responses. ACDase deficiency may cause severe visual impairment.

        Managing Limb Girdle Muscular Dystrophy Type 2D

        The effects of extracellular adenosine triphosphate (eATP), a danger signal, may be amplified in limb girdle muscular dystrophy type 2D (LGMD2D/α-sarcoglycanopathy). Using α-sarcoglycan-null mice, Gazzerro et al (Am J Pathol, 2019 189:354–369) studied the effects of blocking eATP and its downstream P2X purinergic pathway. Pharmacologically inhibiting eATP/P2X purinergic signaling delayed the onset of muscle dystrophy and reduced associated pathology and inflammatory features in vivo. Blocking purinergic pathway may help manage progression of LGMD2D, which is currently untreatable.

        Antibiotics May Alter Bone Development

        Disruption of gut microbiota by antibiotics may dysregulate bone development. Using mice, Hathaway-Schrader et al (Am J Pathol 2019, 189:370–390) studied the effects of antibiotic treatment of the gut microbiota on long-term bone development. Depletion of the gut microbiota by broad-spectrum antibiotics induced host immune responses that further activated osteoclastogenesis to reduce bone mass in male mice. Antibiotic-mediated disruption of the normal gut microbiota may alter osteoimmune crosstalk.

        Tyrosinase Inhibits Lymphangiogenesis

        Mechanisms of endogenous regulation of lymphangiogenesis, the formation of lymphatic vessels from pre-existing lymphatic vessels, are unclear. Using a mouse corneal model, Büttner et al (Am J Pathol 2019, 189:440–448) identified novel potential genes regulating lymphangiogenesis. Low- and high-lymphangiogenic mice were mated and the resulting heterozygous F1 animals intercrossed to generate F2 animals. Quantitative trait loci analysis of five corneal phenotypes in these progenies identified Tyr that encodes tyrosinase, a transmembrane protein in melanocytes, as the strongest locus. Loss of tyrosinase in mice resulted in increased lymphangiogenesis and related processes. Tyrosinase inhibits lymphangiogenesis; targeting tyrosinase or melanin synthesis may help manage lymphangiogenesis-related diseases.

        Managing Shallow Placentation Disorders

        Pro-inflammatory cytokines induce endoplasmic reticulum (ER) stress as well as regulate the key matrix metalloproteinase, MMP-2, required for the invasion of extravillous trophoblasts (EVT) into the decidual endometrium during early pregnancy. Lee et al (Am J Pathol 2019, 189:467–478) studied the link between ER stress and MMP-2 in placental trophoblasts. Pharmacological induction of ER stress in cultured EVT-like cells inhibited MMP-2 mRNA and protein expression, decreased MMP-2 protein secretion and activity, and reduced cell invasiveness. Treatment with a cocktail of pro-inflammatory cytokines suppressed MMP-2 activity and activated the ER stress pathway. Mechanistic data confirmed ER stress–mediated regulation of MMP-2 expression at both the transcriptional and translational levels. Targeting pro-inflammatory cytokines and/or ER stress pathways may help improve morbidity and mortality related to shallow placentation disorders.

        Supplemental Data

        Linked Article

        • Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment
          The American Journal of PathologyVol. 189Issue 2
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            Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus.
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        • Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine–Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy
          The American Journal of PathologyVol. 189Issue 2
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            Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Invasion is mediated partially by matrix metalloproteinases (MMPs). MMP-2 is highly expressed in early pregnancy. MMP activity can be regulated by proinflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether proinflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast before exploring potential regulatory mechanisms.
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        • Antibiotic Perturbation of Gut Microbiota Dysregulates Osteoimmune Cross Talk in Postpubertal Skeletal Development
          The American Journal of PathologyVol. 189Issue 2
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            Commensal gut microbiota–host immune responses are experimentally delineated via gnotobiotic animal models or alternatively by antibiotic perturbation of gut microbiota. Osteoimmunology investigations in germ-free mice, revealing that gut microbiota immunomodulatory actions critically regulate physiologic skeletal development, highlight that antibiotic perturbation of gut microbiota may dysregulate normal osteoimmunological processes. We investigated the impact of antibiotic disruption of gut microbiota on osteoimmune response effects in postpubertal skeletal development.
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        • Tyrosinase Is a Novel Endogenous Regulator of Developmental and Inflammatory Lymphangiogenesis
          The American Journal of PathologyVol. 189Issue 2
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            Lymphangiogenesis is critically involved in tissue fluid balance, graft rejection, and tumor metastasis. Endogenous regulation of lymphangiogenesis is poorly understood. Herein, we use the lymphatic vessel architecture at the limbal border of the normally avascular cornea, a quantitative trait under strong genetic influence, as a model system to identify new candidate genes regulating lymphangiogenesis. Comparing low-lymphangiogenic BALB/cN with high-lymphangiogenic C57BL/6N mice, we performed quantitative trait loci analysis of five phenotypes in a large BALB/cN × C57BL/6N intercross (n = 795) and identified three to eight genome-wide significant loci, the strongest on chromosome 7 containing tyrosinase (Tyr).
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        • The Danger Signal Extracellular ATP Is Involved in the Immunomediated Damage of α-Sarcoglycan–Deficient Muscular Dystrophy
          The American Journal of PathologyVol. 189Issue 2
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            In muscular dystrophies, muscle membrane fragility results in a tissue-specific increase of danger-associated molecular pattern molecules (DAMPs) and infiltration of inflammatory cells. The DAMP extracellular ATP (eATP) released by dying myofibers steadily activates muscle and immune purinergic receptors exerting dual negative effects: a direct damage linked to altered intracellular calcium homeostasis in muscle cells and an indirect toxicity through the triggering of the immune response and inhibition of regulatory T cells.
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