ABSTRACT
Proline-glycine-proline (PGP) and its acetylated form (Ac-PGP) are neutrophil chemoattractants generated by collagen degradation, and they have been shown to play a role in chronic inflammatory disease. However, the mechanism for matrikine regulation in acute inflammation has not been well established. Here, we show that these peptides are actively transported from the lung by the oligopeptide transporter, PEPT2. Following intratracheal instillation of Ac-PGP in a mouse model, there was a rapid decline in concentration of the labeled peptide in the bronchoalveolar lavage (BAL) over time and redistribution to extrapulmonary sites. In vitro knockdown of the PEPT2 transporter in airway epithelia or use of a competitive inhibitor of PEPT2, cefadroxil, significantly reduced uptake of Ac-PGP. Animals that received intratracheal Ac-PGP plus cefadroxil had higher levels of Ac-PGP in BAL and lung tissue. Utilizing an acute LPS-induced lung injury model, we demonstrate that PEPT2 blockade enhanced pulmonary Ac-PGP levels and lung inflammation. We further validated this effect using clinical samples from patients with acute lung injury in coculture with airway epithelia. This is the first study to our knowledge to determine the in vitro and in vivo significance of active matrikine transport as a mechanism of modulating acute inflammation and to demonstrate that it may serve as a potential therapeutic target.
Subject(s)
Acute Lung Injury/immunology , COVID-19 , Cefadroxil/pharmacology , Inflammation/metabolism , Oligopeptides , Proline/analogs & derivatives , Symporters , Animals , Anti-Bacterial Agents/pharmacology , Biological Transport, Active/immunology , COVID-19/immunology , COVID-19/metabolism , Cells, Cultured , Chemotactic Factors/immunology , Chemotactic Factors/pharmacology , Chemotaxis, Leukocyte/immunology , Disease Models, Animal , Extracellular Matrix , Extracellular Matrix Proteins/metabolism , Humans , Mice , Oligopeptides/immunology , Oligopeptides/pharmacology , Proline/immunology , Proline/pharmacology , Symporters/antagonists & inhibitors , Symporters/metabolismABSTRACT
The rush to remote learning during the COVD-19 pandemic has caused instructors to rapidly adapt mechanisms of learning. Here, I describe an online concept mapping activity for membrane transport mechanisms that can be accomplished by students working together remotely and either synchronously or asynchronously.
Subject(s)
Biochemistry/education , COVID-19 , Cell Membrane , Education, Distance , Learning , Pandemics , Biological Transport, Active , Curriculum , Humans , StudentsABSTRACT
The efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection. Recent studies indicated that long-noncoding RNAs expression is highly cell- and stage-specific during T cell development and differentiation, suggesting their potential roles in T cell programs. However, the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified. Through CD8 T cell subsets profiling of lncRNAs, this study found a key lncRNA-Snhg1 with the conserved naivehi-effectorlo-memoryhi expression pattern in CD8 T cells of both mice and human, that can promote memory formation while impeding effector CD8 in acute viral infection. Further, Snhg1 was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Rα membrane location specifically. With the deep mechanism probing, the results show Snhg1-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation, which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival, but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation. Moreover, we performed further study with finding a similar high-low-high expression pattern of human SNHG1/VPS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients. The central role of Snhg1-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Interleukin-7/immunology , Proteins/immunology , RNA, Long Noncoding/immunology , SARS-CoV-2/immunology , Secretory Vesicles/immunology , Signal Transduction/immunology , Animals , Biological Transport, Active , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Humans , Immunologic Memory , Mice , Secretory Vesicles/pathologyABSTRACT
The emerging coronavirus (CoV) pandemic is threatening the public health all over the world. Cytoskeleton is an intricate network involved in controlling cell shape, cargo transport, signal transduction, and cell division. Infection biology studies have illuminated essential roles for cytoskeleton in mediating the outcome of hostâvirus interactions. In this review, we discuss the dynamic interactions between actin filaments, microtubules, intermediate filaments, and CoVs. In one round of viral life cycle, CoVs surf along filopodia on the host membrane to the entry sites, utilize specific intermediate filament protein as co-receptor to enter target cells, hijack microtubules for transportation to replication and assembly sites, and promote actin filaments polymerization to provide forces for egress. During CoV infection, disruption of host cytoskeleton homeostasis and modification state is tightly connected to pathological processes, such as defective cytokinesis, demyelinating, cilia loss, and neuron necrosis. There are increasing mechanistic studies on cytoskeleton upon CoV infection, such as viral proteinâcytoskeleton interaction, changes in the expression and post-translation modification, related signaling pathways, and incorporation with other host factors. Collectively, these insights provide new concepts for fundamental virology and the control of CoV infection.