Key Points
Dgkζ deficiency protects from the induction of inflammatory arthritis.
Dgkζ deficiency limits activation of proinflammatory macrophages.
Dgkζ deficiency reduces phosphorylation of STAT1 and STAT3 in activated macrophages.
Abstract
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) ζ, 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, Dgkζ deficiency results in reduced production of TNF-α, IL-6, and IL-1β and in limited M1 macrophage polarization. Mechanistically, Dgkζ deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgkζ levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that Dgkζ induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of Dgkζ–DAG/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS.
Footnotes
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.
The online version of this article contains supplemental material.
- Received June 25, 2019.
- Accepted November 4, 2019.
- Copyright © 2019 by The American Association of Immunologists, Inc.