Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury

Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury

Bibliographic Details
Main Author: Church, Jamie Stoddard
Language:English
Published: The Ohio State University / OhioLINK 2016
Subjects:
Neurobiology
Neurosciences
Immunology
TLR4
macrophage
oligodendrocyte
iron regulation
phagocytosis
spinal cord injury
demyelination
oligogenesis
oligodendrocyte progenitor cell
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1468501949
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1468501949
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Neurobiology
Neurosciences
Immunology
TLR4
macrophage
oligodendrocyte
iron regulation
phagocytosis
spinal cord injury
demyelination
oligogenesis
oligodendrocyte progenitor cell
spellingShingle Neurobiology
Neurosciences
Immunology
TLR4
macrophage
oligodendrocyte
iron regulation
phagocytosis
spinal cord injury
demyelination
oligogenesis
oligodendrocyte progenitor cell
Church, Jamie Stoddard
Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury
author Church, Jamie Stoddard
author_facet Church, Jamie Stoddard
author_sort Church, Jamie Stoddard
title Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury
title_short Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury
title_full Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury
title_fullStr Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury
title_full_unstemmed Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury
title_sort toll-like receptor 4 regulates intraspinal and peripheral responses after spinal cord injury
publisher The Ohio State University / OhioLINK
publishDate 2016
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1468501949
work_keys_str_mv AT churchjamiestoddard tolllikereceptor4regulatesintraspinalandperipheralresponsesafterspinalcordinjury
_version_ 1719440456252653568
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu14685019492021-08-03T06:37:21Z Toll-like Receptor 4 Regulates Intraspinal and Peripheral Responses after Spinal Cord Injury Church, Jamie Stoddard Neurobiology Neurosciences Immunology TLR4 macrophage oligodendrocyte iron regulation phagocytosis spinal cord injury demyelination oligogenesis oligodendrocyte progenitor cell Traumatic spinal cord injury (SCI) disrupts not only the central nervous system, but also peripheral homeostatic processes. Macrophages are immune cells that accumulate in the SCI lesion and peripheral organs after injury and respond to a variety of endogenous ligands, including damage-associated molecular patterns (DAMPs) generated by trauma to the spinal cord. Ligands for the innate immune receptor toll-like receptor 4 (TLR4) expressed on macrophages are present in the intraspinal lesion and in peripheral organs after injury. DAMPs such as HMGB1 and heat-shock proteins can bind TLR4, while bacteria originating in the gut can translocate and activate peripheral TLR4. TLR4 signaling regulates key macrophage functions that influence outcome after SCI including iron regulation, phagocytosis, and expression of cytokines. Thus it is likely that manipulating this single receptor will have a profound effect on intraspinal and peripheral responses after SCI.After SCI, DAMPs initiate secondary injury processes including apoptosis and inflammation. Acutely, oligodendrocytes (OLs) and their progenitor cells (OPCs) are lost, followed by robust OPC proliferation, formation of new OLs, and remyelination of bare axons. Previously, our group showed that macrophage TLR4 signaling promoted beneficial OL lineage cell responses in the intact spinal cord and mice deficient for TLR4 signaling (TLR4d) displayed reduced white matter sparing after SCI. Here, we determined that reduced white matter sparing in TLR4d mice was due to reduced OL lineage survival and replacement (Chapter 2). These differences in OL survival and replacement were accompanied by alterations in macrophage iron regulation and myelin debris phagocytosis, cytokine and growth factor expression, and axon survival, processes which all directly impact OL and OPC responses. We next asked whether exogenous intraspinal TLR4 activation would enhance oligogenesis and remyelination in a lysolecithin demyelination model (Chapter 3). E6020, a synthetic TLR4 agonist, accelerated macrophage activation and myelin debris phagocytosis and degradation. These alterations in macrophage function were followed by increased Schwann cell recruitment, axon sparing, and remyelination by both OLs and Schwann cells. Together, these studies indicate that intraspinal TLR4 signaling alters macrophage functions and promotes beneficial OL lineage cell responses in the injured spinal cord.Anemia and pressure ulcers are two common iron-related comorbidities with SCI. Because TLR4 is an innate immune receptor and its signaling in macrophages regulates systemic iron during pathogen invasion we investigated whether TLR4 signaling influenced peripheral iron dysregulation after SCI (Chapter 4). TLR4d mice displayed systemic iron distribution after injury characteristic of iron deficiency anemia, while C57BL/6 mice showed increased hepatic iron consistent with anemia of chronic inflammation. These data demonstrate peripheral iron homeostasis changes after SCI differ between mouse strains, and TLR4 signaling coordinates inter-organ iron redistribution.In conclusion, my graduate work shows that intraspinal TLR4 signaling alters macrophage iron regulation and myelin debris phagocytosis, and influences each stage of OL lineage cell progression. Peripherally, iron homeostasis in major iron regulatory organs changes after SCI, and TLR4 signaling is a key player in coordinating this response. Altogether, these findings indicate that TLR4 signaling is a master regulator of intraspinal and peripheral responses after SCI. 2016-12-28 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1468501949 http://rave.ohiolink.edu/etdc/view?acc_num=osu1468501949 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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