Leveraging TREM2 agonism to enhance efferocytosis in lupus

Summary: Efficient clearance of apoptotic cells, known as efferocytosis, is crucial for maintaining self-tolerance. Impaired efferocytosis is linked to the progression of inflammatory disorders such as systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE). Uncleared apoptotic cells accumulate in peripheral tissues as a contributing source of inflammatory stimuli to enhances type-I interferon production, further promoting disease progression. Lipid metabolism plays a significant regulatory role in macrophage efferocytosis and leads to macrophage reprogramming to promote resolution of inflammation. Even so, the mechanisms that control macrophage metabolism during efferocytosis in lupus-like inflammatory conditions are not yet fully understood. Given the potent immune-regulatory function of lipid metabolism on macrophages induced by efferocytosis, we aimed to augment efferocytosis to reprogram macrophages to ultimately support anti-inflammatory responses. We identified TREM2-expressing macrophages as a candidate cell population to control inflammation and thus developed a therapeutically relevant TREM2 agonist to interrogate the effects of TREM2 signaling under inflammatory conditions. Here, we demonstrate that macrophages treated with a TREM2 agonist show enhanced efferocytosis <i>in vitro</i> and <i>ex vivo</i> using macrophages derived from peripheral blood monocytes or isolated from human skin, respectively. We found that this agonist rescued defective efferocytosis by macrophages cultured in the presence of serum from patients with SLE or in the presence of IFN-β without altering phagocytosis of live cells. Mechanistically, TREM2 agonism created a heightened dependency on lipid metabolism leading to enhanced efferocytosis, a process itself known to support pro-resolution phenotypes in macrophages. The insights gained from our investigation present promising avenues for therapeutic intervention in SLE and CLE, emphasizing the manipulation of macrophage metabolism and subsequent effector functions. Jessica L. Shannon¹, Zhiwei Fang¹, Ellen Gowans², James Hunt², Tatiana Ort¹, Rafael de Queiroz Prado¹ 1. Early Respiratory & Immunology, AstraZeneca Pharmaceuticals LP, Gaithersburg, MD, United States. 2. Biologics Engineering, AstraZeneca PLC, Cambridge, England, United Kingdom. Adaptive and Auto-Immunity