Mechanisms Driving Innate Regulation Of Immunological Tolerance To Apoptotic Cells Preventing Autoimmunity

Hdl Handle:
http://hdl.handle.net/10675.2/583170
Title:
Mechanisms Driving Innate Regulation Of Immunological Tolerance To Apoptotic Cells Preventing Autoimmunity
Authors:
Shinde, Rahul
Abstract:
Innate immune responses to apoptosis are crucial for self-tolerance. Although upstream signals promoting recognition and processing of apoptotic cells have been extensively studied, downstream molecular mechanisms driving innate regulation of apoptotic cell responses are less understood. Here we report an unsuspected discovery that the ligand dependent transcription factor aryl hydrocarbon receptor (AhR) initiates tolerogenic signaling to apoptotic cells and prevents systemic autoimmunity. AhR is known to control xenobiotic stress responses and recently has been linked to modulation of T cell and DC function. In this study, we found that apoptotic cells induced AhR signals in tissueresident MΦs and activation was dependent on DNA from apoptotic cells. AhR was required for apoptotic cell driven immune suppression as deletion of AhR abrogated IL-10, promoting the inflammatory cytokines IL-6 and IL-12, while supplementing IL-10 restored the regulatory phenotype of MΦs. Moreover, inhibition of the AhR pathway fundamentally altered immune responses to apoptotic cells resulting in proinflammatory cytokine production, increased effector T cell responses and abrogation of long-term allograft tolerance to apoptotic cell associated antigens. Further, mice lacking AhR developed spontaneous autoimmunity characterized by excessive macrophage and lymphocyte activation associated with renal pathology. Deficiency of AhR led to breakdown in tolerance with rapid increases in anti-dsDNA and anti-histone antibody responses after chronic challenge with apoptotic cells. Similarly, when SLE-prone mice were treated with AhR antagonist they exhibited significantly elevated humoral auto-reactivity, augmented inflammatory cytokine production in MΦs, intensified autoreactive B and T cells, renal pathology, and mortality; while AhR agonist treatment resulted in significant reduction of autoimmune disease parameters compared to control mice. Collectively, the data demonstrate apoptotic cell activation of AhR is a key mechanism suppressing anti-apoptotic cell inflammatory responses preventing autoimmunity.
Affiliation:
Department of Neuroscience and Regenerative Medicine
Issue Date:
Aug-2015
URI:
http://hdl.handle.net/10675.2/583170
Type:
Dissertation
Appears in Collections:
Theses and Dissertations; Department of Neuroscience & Regenerative Medicine Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorShinde, Rahulen
dc.date.accessioned2015-12-03T14:31:41Zen
dc.date.available2015-12-03T14:31:41Zen
dc.date.issued2015-08en
dc.identifier.urihttp://hdl.handle.net/10675.2/583170en
dc.description.abstractInnate immune responses to apoptosis are crucial for self-tolerance. Although upstream signals promoting recognition and processing of apoptotic cells have been extensively studied, downstream molecular mechanisms driving innate regulation of apoptotic cell responses are less understood. Here we report an unsuspected discovery that the ligand dependent transcription factor aryl hydrocarbon receptor (AhR) initiates tolerogenic signaling to apoptotic cells and prevents systemic autoimmunity. AhR is known to control xenobiotic stress responses and recently has been linked to modulation of T cell and DC function. In this study, we found that apoptotic cells induced AhR signals in tissueresident MΦs and activation was dependent on DNA from apoptotic cells. AhR was required for apoptotic cell driven immune suppression as deletion of AhR abrogated IL-10, promoting the inflammatory cytokines IL-6 and IL-12, while supplementing IL-10 restored the regulatory phenotype of MΦs. Moreover, inhibition of the AhR pathway fundamentally altered immune responses to apoptotic cells resulting in proinflammatory cytokine production, increased effector T cell responses and abrogation of long-term allograft tolerance to apoptotic cell associated antigens. Further, mice lacking AhR developed spontaneous autoimmunity characterized by excessive macrophage and lymphocyte activation associated with renal pathology. Deficiency of AhR led to breakdown in tolerance with rapid increases in anti-dsDNA and anti-histone antibody responses after chronic challenge with apoptotic cells. Similarly, when SLE-prone mice were treated with AhR antagonist they exhibited significantly elevated humoral auto-reactivity, augmented inflammatory cytokine production in MΦs, intensified autoreactive B and T cells, renal pathology, and mortality; while AhR agonist treatment resulted in significant reduction of autoimmune disease parameters compared to control mice. Collectively, the data demonstrate apoptotic cell activation of AhR is a key mechanism suppressing anti-apoptotic cell inflammatory responses preventing autoimmunity.en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectApoptosisen
dc.subjectIL10 Protein, Humanen
dc.subjectInflammationen
dc.subjectSelf Toleranceen
dc.subjectDNAen
dc.subjectMacrophagesen
dc.titleMechanisms Driving Innate Regulation Of Immunological Tolerance To Apoptotic Cells Preventing Autoimmunityen
dc.typeDissertationen
dc.contributor.departmentDepartment of Neuroscience and Regenerative Medicineen
dc.description.advisorMcGaha, Tracyen
dc.description.committeeMunn. David; Manicassamy, Santhakumar; Horuzsko,Anatolij; Pacholczyk, Rafalen
dc.description.degreeDoctor of Philosophy with a Major in Molecular Medicineen
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