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      Neutrophil-Mediated Immunopathology and Matrix Metalloproteinases in Central Nervous System – Tuberculosis

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          Abstract

          Tuberculosis (TB) remains one of the leading infectious killers in the world, infecting approximately a quarter of the world’s population with the causative organism Mycobacterium tuberculosis ( M. tb). Central nervous system tuberculosis (CNS-TB) is the most severe form of TB, with high mortality and residual neurological sequelae even with effective TB treatment. In CNS-TB, recruited neutrophils infiltrate into the brain to carry out its antimicrobial functions of degranulation, phagocytosis and NETosis. However, neutrophils also mediate inflammation, tissue destruction and immunopathology in the CNS. Neutrophils release key mediators including matrix metalloproteinase (MMPs) which degrade brain extracellular matrix (ECM), tumor necrosis factor (TNF)-α which may drive inflammation, reactive oxygen species (ROS) that drive cellular necrosis and neutrophil extracellular traps (NETs), interacting with platelets to form thrombi that may lead to ischemic stroke. Host-directed therapies (HDTs) targeting these key mediators are potentially exciting, but currently remain of unproven effectiveness. This article reviews the key role of neutrophils and neutrophil-derived mediators in driving CNS-TB immunopathology.

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          Most cited references266

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          Neutrophil extracellular traps kill bacteria.

          Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.
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            Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.

            It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.
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              How matrix metalloproteinases regulate cell behavior.

              The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                12 January 2022
                2021
                : 12
                : 788976
                Affiliations
                [1] 1 Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore
                [2] 2 Institute for Infection and Immunity, St George’s, University of London , London, United Kingdom
                [3] 3 Division of Infectious Diseases, Department of Medicine, National University Hospital , Singapore, Singapore
                [4] 4 Institute for Health Innovation and Technology (iHealthtech), National University of Singapore , Singapore, Singapore
                Author notes

                Edited by: Buka Samten, The University of Texas Health Science Center at Tyler, United States

                Reviewed by: Meraj Alam Khan, Hospital for Sick Children, Canada; Hongfei Duan, Capital Medical University, China

                *Correspondence: Catherine W. M. Ong, Catherine_wm_ong@ 123456nuhs.edu.sg

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2021.788976
                8789671
                35095865
                23934e21-03a8-4265-8902-b985d8f20811
                Copyright © 2022 Poh, Loh, Friedland and Ong

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 October 2021
                : 20 December 2021
                Page count
                Figures: 8, Tables: 2, Equations: 0, References: 266, Pages: 24, Words: 11490
                Funding
                Funded by: National Medical Research Council , doi 10.13039/501100001349;
                Categories
                Immunology
                Review

                Immunology
                tuberculosis,central nervous system tuberculosis,neutrophils,matrix metalloproteinases,stroke,host-directed therapy

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