Stroke-induced lipocalin-2-expressing red pulp macrophages reprogram peripheral immunity

Abstract

Acute ischemic stroke (AIS) induces profound systemic immune alterations that contribute to infection susceptibility. Here, we identify lipocalin-2 (LCN-2) as a rapidly induced and conserved regulator of stroke-associated immunosuppression. Using 3-MACE-Seq, cytokine profiling, and immunofluorescence in C57BL/6J mice subjected to transient middle cerebral artery occlusion (tMCAO), we show that LCN-2 is strongly upregulated in splenic red pulp macrophages (RPMs) within 24 hours and again 7 days post-tMCAO. LCN-2-expressing RPMs form immunological synapses with CD3+ T cells, thereby impacting T cell trafficking. Recombinant LCN-2 directly reprogrammed T cells and monocytes toward hyporesponsive, tolerogenic phenotypes by suppressing inflammatory cytokines, impairing chemotaxis, enhancing phagocytosis, and uncoupling oxidative burst. Human spleens likewise displayed LCN-2-expressing CD68+ RPMs, and LCN-2 preconditioning of monocytes reproduced reduced HLA-DR, CD80, CD206, and ROS with increased uptake of E. coli bioparticles. These findings identify LCN-2 signaling as a central orchestrator of stroke-induced peripheral immunoreprogramming and a potential therapeutic target to mitigate post-stroke immunodepression. SummaryAcute ischemic stroke induces LCN-2 in splenic red pulp macrophages, which reprogram T cells and monocytes toward tolerogenic, hyporesponsive states. Mouse and human data identify LCN-2 as a driver of peripheral immunodepression and a potential target to reduce infection risk. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/733904v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@fb0caforg.highwire.dtl.DTLVardef@1fdcd41org.highwire.dtl.DTLVardef@1ae99b0org.highwire.dtl.DTLVardef@1ec0837_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG