TY - JOUR
T1 - Diacylglycerol kinase Z regulates macrophage responses in juvenile arthritis and cytokine Storm syndrome mouse models
AU - Mahajan, Sahil
AU - Mellins, Elizabeth D.
AU - Faccio, Roberta
N1 - Funding Information:
This work was supported by National Institutes of Health Grants R01 AR053628 (to R.F.), R01 AR066551 (to R.F.), and R01 AR061297 (to E.D.M.) and grants from Shriners Hospital 85100 (to R.F.) and Siteman Cancer Center (to R.F.). Histological analysis was performed through the Histology Core at the Washington University Musculoskeletal Research Center, supported by the National Institutes of Health P30 Grants AR057235 and P30 AR074992.
Funding Information:
This work was supported by National Institutes of Health Grants R01 AR053628 (to R.F.), R01 AR066551 (to R.F.), and R01 AR061297 (to E.D.M.) and grants from Shriners Hospital 85100 (to R.F.) and Siteman Cancer Center (to R.F.). Histological analysis was performed through the Histology Core at the Washington University Musculoskeletal Research Center, supported by the National Institutes of Health P30 Grants AR057235 and P30 AR074992. We thank Dr. Biancamaria Ricci, Dr. Zhengfeng Yang, Dr. Won Jong Jin, and Ali Zamani for technical help and suggestions.
Publisher Copyright:
Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2020
Y1 - 2020
N2 - Dysregulation of monocyte and macrophage responses are often observed in children with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS), a potentially fatal complication of chronic rheumatic diseases. Both conditions are associated with activation of TLR signaling in monocyte and macrophage lineage cells, leading to overwhelming inflammatory responses. Despite the importance of TLR engagement in activating proinflammatory macrophages, relatively little is known about activation of intrinsic negative regulatory pathways to attenuate excessive inflammatory responses. In this study, we demonstrate that loss of diacylglycerol (DAG) kinase (Dgk) z, an enzyme which converts DAG into phosphatidic acid, limits inflammatory cytokine production in an arthritic mouse model dependent on TLR2 signaling and in a CSS mouse model dependent on TLR9 signaling. In vitro, Dgkz deficiency results in reduced production of TNF-a, IL-6, and IL-1b and in limited M1 macrophage polarization. Mechanistically, Dgkz deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgkz levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that Dgkz induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of Dgkz–DAG/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS. The Journal of Immunology, 2020, 204: 137–146.
AB - Dysregulation of monocyte and macrophage responses are often observed in children with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS), a potentially fatal complication of chronic rheumatic diseases. Both conditions are associated with activation of TLR signaling in monocyte and macrophage lineage cells, leading to overwhelming inflammatory responses. Despite the importance of TLR engagement in activating proinflammatory macrophages, relatively little is known about activation of intrinsic negative regulatory pathways to attenuate excessive inflammatory responses. In this study, we demonstrate that loss of diacylglycerol (DAG) kinase (Dgk) z, an enzyme which converts DAG into phosphatidic acid, limits inflammatory cytokine production in an arthritic mouse model dependent on TLR2 signaling and in a CSS mouse model dependent on TLR9 signaling. In vitro, Dgkz deficiency results in reduced production of TNF-a, IL-6, and IL-1b and in limited M1 macrophage polarization. Mechanistically, Dgkz deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgkz levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that Dgkz induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of Dgkz–DAG/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS. The Journal of Immunology, 2020, 204: 137–146.
UR - http://www.scopus.com/inward/record.url?scp=85076876680&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1900721
DO - 10.4049/jimmunol.1900721
M3 - Article
C2 - 31801815
AN - SCOPUS:85076876680
SN - 0022-1767
VL - 204
SP - 137
EP - 146
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -