Project description:Macrophages are essential for pathogen clearance and to preserve tissue homeostasis, yet the molecular regulators of this equilibrium remain incompletely defined. Here, we identify SAILR, a primate-specific long noncoding RNA (lncRNA), as a critical modulator of macrophage viability under infection conditions. SAILR is induced during monocyte-to-macrophage differentiation, but rapidly downregulated upon bacterial challenge in an NFκB-dependent manner. In both naïve and immune-activated macrophages, SAILR dampens the expression of adhesion, phagocytosis and invasion factors, including SIGLEC1 and MMP7. During Salmonella Typhimurium infection, depletion of SAILR sensitizes macrophages to apoptosis, resulting in loss of intracellular replication niches and reduced bacterial recovery. Conversely, enforced SAILR expression promotes macrophage survival and increases intracellular pathogen burden. Mechanistically, SAILR interacts with the anti-apoptotic adaptor protein 14-3-3β to support macrophage survival. Notably, downregulation of SAILR is mirrored in circulating immune cells from patients with severe COVID-19 and sepsis. Together, our findings position SAILR as a central regulator linking macrophage survival to host-pathogen interaction and disease pathophysiology. Long noncoding RNAs (lncRNAs) are a class of regulatory molecules whose roles in the immune system remain poorly understood. In this study, we identify a human-specific lncRNA named SAILR that modulates the viability of macrophages - immune cells essential for pathogen clearance. SAILR interacts with the adaptor protein 14-3-3β and is rapidly downregulated upon bacterial infection, which sensitizes macrophages to cell death. This may limit the formation of intracellular niches that support pathogen propagation. Reduced SAILR levels in patients suffering from severe infections (sepsis and COVID-19) further suggest clinical relevance. Together, our findings reveal an RNA-based mechanism linking macrophage survival control to host defense and suggest SAILR as a potential diagnostic marker or therapeutic target in infectious and inflammatory diseases.

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LINC01857 regulates antigen-presenting cell viability and antimicrobial defense in humans

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