Diacylglycerol kinase Z regulates macrophage responses in juvenile arthritis and cytokine Storm syndrome mouse models

Sahil Mahajan, Elizabeth D. Mellins, Roberta Faccio

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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) 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.

Original languageEnglish
Pages (from-to)137-146
Number of pages10
JournalJournal of Immunology
Volume204
Issue number1
DOIs
StatePublished - 2020

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