OP0329 PLCGAMMA2/TMEM178 DEPENDENT PATHWAY IN MYELOID CELLS MODULATES THE PATHOGENESIS OFCYTOKINE STORM SYNDROME

Background Cytokine storm syndrome (CSS) is a life-threatening condition, observed in several rheumatic diseases, and a well-known complication of systemic juvenile idiopathic arthritis (sJIA) (1). Defects in T cell cytotoxicity leading to their excessive activation are major contributors to CSS development. However, dysregulated innate immune responses are also observed (2). The role of monocytes and macrophages as drivers of CSS, regardless of T cells, and the signaling pathways regulating monocyte/macrophage responses, have not been formally investigated. Objectives The goal of this study was to determine the contribution of monocytes/macrophages to the development of CSS and analyze the signaling pathways that lead to aberrant monocyte/macrophage pro-inflammatory responses using animal models of the disease and patient samples. Methods To study the involvement of monocytes/macrophages in a T cell-dependent model of CSS we treated LCMV-infected Perforin-/- mice with clodronate-liposomes or neutralizing anti-CSF1Ab prior to disease initiation. Similar depletion experiments were performed in a T-cell independent CSS model consisting of five injections of the TLR9 agonist CpG-1826 into WT mice. Myeloid cell contribution to CSS was assessed in mice with LysMCre-driven deletion of Plcγ2 or global deletion of Tmem178, a downstream Plcγ2 target gene specifically expressed in macrophages. Presence of immune infiltrates in liver and spleen was evaluated by FACS analysis and immunohistochemistry, circulating inflammatory cytokine levels were detected by ELISA, multi-organ damage was evaluated by histology. Results Depletion of monocytes/macrophages during early stages of CSS reduces mortality and inflammatory cytokine levels in both T-cell dependent and independent CSS models. Activation of Plcγ2 in myeloid cells controls CSS development by driving macrophage pro-inflammatory responses. Intriguingly, the Plcγ2 downstream effector Tmem178 acts in a negative feedback loop to restrain inflammatory cytokine production and protect from CSS development. Highlighting the clinical relevance, Tmem178 levels are reduced in macrophages from mice with CSS or exposed to sJIA patient plasma with active disease. Conclusion Macrophages are key drivers of CSS initiation. We identified a novel Plcγ2/Tmem178 axis as a modulator of inflammatory cytokine production by monocytes/macrophages in CSS. Reduced Tmem178 levels are observed in sJIA and might be responsible for the increased macrophage pro-inflammatory responses. References [1] Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin North Am. 2012;59:329-44. [2] Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12:259-68. Acknowledgement This work was supported by R01 AR053628 and R01 AR066551 from National Institute of Health (NIH) to Roberta Faccio and Shriners Hospital 85100 to Roberta Faccio. Disclosure of Interests Sahil Mahajan: None declared, Zhengfeng Yang: None declared, Elisabeth Mellins Grant/research support from: Novartis and GlaxoSmithKline., roberta faccio: None declared