Macrophage dependent pathways modulate the pathogenesis of cytokine storm syndrome

Abstract

Abstract Cytokine storm syndromes (CSS) are life-threatening conditions characterized by excessive activation of T cells, accumulation of well-differentiated macrophages in various organs and exuberant release of inflammatory cytokines. CSS are associated with a wide variety of infectious and noninfectious diseases, often occurring in patients with familial hemophagocytic lymphohistiocytosis and systemic juvenile idiopathic arthritis (sJIA). Although increased number of macrophages is observed in CSS, their role in disease initiation has never been investigated. Here we report that depletion of macrophages at disease onset decreases lethality and limits CSS in two clinically relevant animal models. Mechanistic studies reveal that phospholipase C gamma 2 (Plcʏ2) is critical for macrophage responses during CSS. To dissect how Plcʏ2 induces macrophage activation during CSS, we evaluated two Plcʏ2 downstream pathways, namely calcium and diacylglycerol (DAG). Calcium and DAG levels are tightly controlled by expression of Tmem178, a Plcʏ2-dependent protein and negative regulator of calcium fluxes, and Dgkζ, an enzyme converting DAG into phosphatidic acid, respectively. Intriguingly, by using Tmem178−/− or Dgkζ−/− mouse models, we discovered that calcium and DAG exert opposite effects, with increased calcium augmenting macrophage activation and CSS severity while accumulation of DAG limiting these excessive inflammatory responses. Importantly, macrophages exposed to plasma from sJIA patients that are at risk of developing CSS show skewing toward increased calcium and reduced DAG, via modulation of Tmem178 and Dgkζ expression. In conclusion our data indicate a potential role for macrophage-based therapies for CSS.