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Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells

Inefficient and abnormal clearance of apoptotic cells (efferocytosis) contributes to systemic autoimmune disease in humans and mice, and inefficient chromosomal DNA degradation by DNAse II leads to systemic polyarthritis and a cytokine storm. By contrast, efficient clearance allows immune homeostasi...

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Detalles Bibliográficos
Autores principales: Trahtemberg, Uriel, Mevorach, Dror
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661053/
https://www.ncbi.nlm.nih.gov/pubmed/29118755
http://dx.doi.org/10.3389/fimmu.2017.01356
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author Trahtemberg, Uriel
Mevorach, Dror
author_facet Trahtemberg, Uriel
Mevorach, Dror
author_sort Trahtemberg, Uriel
collection PubMed
description Inefficient and abnormal clearance of apoptotic cells (efferocytosis) contributes to systemic autoimmune disease in humans and mice, and inefficient chromosomal DNA degradation by DNAse II leads to systemic polyarthritis and a cytokine storm. By contrast, efficient clearance allows immune homeostasis, generally leads to a non-inflammatory state for both macrophages and dendritic cells (DCs), and contributes to maintenance of peripheral tolerance. As many as 3 × 10(8) cells undergo apoptosis every hour in our bodies, and one of the primary “eat me” signals expressed by apoptotic cells is phosphatidylserine (PtdSer). Apoptotic cells themselves are major contributors to the “anti-inflammatory” nature of the engulfment process, some by secreting thrombospondin-1 (TSP-1) or adenosine monophosphate and possibly other immune modulating “calm-down” signals that interact with macrophages and DCs. Apoptotic cells also produce “find me” and “tolerate me” signals to attract and immune modulate macrophages and DCs that express specific receptors for some of these signals. Neither macrophages nor DCs are uniform, and each cell type may variably express membrane proteins that function as receptors for PtdSer or for opsonins like complement or opsonins that bind to PtdSer, such as protein S and growth arrest-specific 6. Macrophages and DCs also express scavenger receptors, CD36, and integrins that function via bridging molecules such as TSP-1 or milk fat globule-EGF factor 8 protein and that differentially engage in various multi-ligand interactions between apoptotic cells and phagocytes. In this review, we describe the anti-inflammatory and pro-homeostatic nature of apoptotic cell interaction with the immune system. We do not review some forms of immunogenic cell death. We summarize the known apoptotic cell signaling events in macrophages and DCs that are related to toll-like receptors, nuclear factor kappa B, inflammasome, the lipid-activated nuclear receptors, Tyro3, Axl, and Mertk receptors, as well as induction of signal transducer and activator of transcription 1 and suppressor of cytokine signaling that lead to immune system silencing and DC tolerance. These properties of apoptotic cells are the mechanisms that enable their successful use as therapeutic modalities in mice and humans in various autoimmune diseases, organ transplantation, graft-versus-host disease, and sepsis.
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spelling pubmed-56610532017-11-08 Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells Trahtemberg, Uriel Mevorach, Dror Front Immunol Immunology Inefficient and abnormal clearance of apoptotic cells (efferocytosis) contributes to systemic autoimmune disease in humans and mice, and inefficient chromosomal DNA degradation by DNAse II leads to systemic polyarthritis and a cytokine storm. By contrast, efficient clearance allows immune homeostasis, generally leads to a non-inflammatory state for both macrophages and dendritic cells (DCs), and contributes to maintenance of peripheral tolerance. As many as 3 × 10(8) cells undergo apoptosis every hour in our bodies, and one of the primary “eat me” signals expressed by apoptotic cells is phosphatidylserine (PtdSer). Apoptotic cells themselves are major contributors to the “anti-inflammatory” nature of the engulfment process, some by secreting thrombospondin-1 (TSP-1) or adenosine monophosphate and possibly other immune modulating “calm-down” signals that interact with macrophages and DCs. Apoptotic cells also produce “find me” and “tolerate me” signals to attract and immune modulate macrophages and DCs that express specific receptors for some of these signals. Neither macrophages nor DCs are uniform, and each cell type may variably express membrane proteins that function as receptors for PtdSer or for opsonins like complement or opsonins that bind to PtdSer, such as protein S and growth arrest-specific 6. Macrophages and DCs also express scavenger receptors, CD36, and integrins that function via bridging molecules such as TSP-1 or milk fat globule-EGF factor 8 protein and that differentially engage in various multi-ligand interactions between apoptotic cells and phagocytes. In this review, we describe the anti-inflammatory and pro-homeostatic nature of apoptotic cell interaction with the immune system. We do not review some forms of immunogenic cell death. We summarize the known apoptotic cell signaling events in macrophages and DCs that are related to toll-like receptors, nuclear factor kappa B, inflammasome, the lipid-activated nuclear receptors, Tyro3, Axl, and Mertk receptors, as well as induction of signal transducer and activator of transcription 1 and suppressor of cytokine signaling that lead to immune system silencing and DC tolerance. These properties of apoptotic cells are the mechanisms that enable their successful use as therapeutic modalities in mice and humans in various autoimmune diseases, organ transplantation, graft-versus-host disease, and sepsis. Frontiers Media S.A. 2017-10-25 /pmc/articles/PMC5661053/ /pubmed/29118755 http://dx.doi.org/10.3389/fimmu.2017.01356 Text en Copyright © 2017 Trahtemberg and Mevorach. http://creativecommons.org/licenses/by/4.0/ 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) or licensor 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.
spellingShingle Immunology
Trahtemberg, Uriel
Mevorach, Dror
Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells
title Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells
title_full Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells
title_fullStr Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells
title_full_unstemmed Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells
title_short Apoptotic Cells Induced Signaling for Immune Homeostasis in Macrophages and Dendritic Cells
title_sort apoptotic cells induced signaling for immune homeostasis in macrophages and dendritic cells
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661053/
https://www.ncbi.nlm.nih.gov/pubmed/29118755
http://dx.doi.org/10.3389/fimmu.2017.01356
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