TY - JOUR
T1 - SAG/RBX2 E3 Ubiquitin Ligase Differentially Regulates Inflammatory Responses of Myeloid Cell Subsets
AU - Xiong, Xiufang
AU - Mathewson, Nathan D.
AU - Li, Hua
AU - Tan, Mingjia
AU - Fujiwara, Hideaki
AU - Li, Haomin
AU - Reddy, Pavan
AU - Sun, Yi
N1 - Funding Information:
This work is supported by National Key R&D Program of China (2016YFA0501800) to YS and XX; by National Cancer Institute grants (R01 CA156744 and CA171277) to YS; and by National Institutes of Health grants (National Heart, Lung and Blood Institute, HL-090775 and HL-128046; and National Cancer Institute, CA-173878) to PR. NM was supported by a Post-doctoral Fellowship, PF-17-042-01–LIB, from the American Cancer Society.
Publisher Copyright:
© Copyright © 2018 Xiong, Mathewson, Li, Tan, Fujiwara, Li, Reddy and Sun.
PY - 2018/12/6
Y1 - 2018/12/6
N2 - Macrophages form an important component of the innate immune system and serve as first responders against invading pathogens. While pathways critical for initiation of inflammatory responses between macrophages and other LysM+ myeloid cells are largely similar, it remains unknown whether a specific pathway has differential effects on inflammatory responses mediated between these cells. Recent studies demonstrated that depletion of SAG (Sensitive to Apoptosis Gene), an E3 ubiquitin ligase, blocked inflammatory responses generated by macrophages and dendritic cells in response to LPS in cell culture settings. However, the in vivo role of Sag on modulation of macrophages and neutrophil is not known. Here we generated LysM-Cre/Sagfl/fl mice with selective Sag deletion in myeloid lineage, and found that in contrast to in vitro observations, LysM-Cre/Sagfl/fl mice showed increased serum levels of proinflammatory cytokines and enhanced mortality in response to LPS. Interestingly, while Sag−/− macrophages released less proinflammatory cytokines, Sag−/− neutrophils released more. Mechanistically, expression of a list of genes response to LPS was significantly altered in bone marrow cells from LysM-Cre+/Sagfl/fl mice after LPS challenge. Specifically, induction by LPS of myeloperoxidase (Mpo), a key neutrophil enzyme, and Elane, neutrophil expressed elastase, was significantly decreased upon Sag depletion. Collectively, our study revealed that Sag plays a differential role in the activation of macrophages and neutrophils.
AB - Macrophages form an important component of the innate immune system and serve as first responders against invading pathogens. While pathways critical for initiation of inflammatory responses between macrophages and other LysM+ myeloid cells are largely similar, it remains unknown whether a specific pathway has differential effects on inflammatory responses mediated between these cells. Recent studies demonstrated that depletion of SAG (Sensitive to Apoptosis Gene), an E3 ubiquitin ligase, blocked inflammatory responses generated by macrophages and dendritic cells in response to LPS in cell culture settings. However, the in vivo role of Sag on modulation of macrophages and neutrophil is not known. Here we generated LysM-Cre/Sagfl/fl mice with selective Sag deletion in myeloid lineage, and found that in contrast to in vitro observations, LysM-Cre/Sagfl/fl mice showed increased serum levels of proinflammatory cytokines and enhanced mortality in response to LPS. Interestingly, while Sag−/− macrophages released less proinflammatory cytokines, Sag−/− neutrophils released more. Mechanistically, expression of a list of genes response to LPS was significantly altered in bone marrow cells from LysM-Cre+/Sagfl/fl mice after LPS challenge. Specifically, induction by LPS of myeloperoxidase (Mpo), a key neutrophil enzyme, and Elane, neutrophil expressed elastase, was significantly decreased upon Sag depletion. Collectively, our study revealed that Sag plays a differential role in the activation of macrophages and neutrophils.
KW - LPS
KW - SAG ubiquitin ligase
KW - inflammatory response
KW - macrophage
KW - neutrophil
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U2 - 10.3389/fimmu.2018.02882
DO - 10.3389/fimmu.2018.02882
M3 - Article
C2 - 30574150
AN - SCOPUS:85058889261
VL - 9
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 2882
ER -