A gradient of immune complexes induces directional migration and a lupus-associated transcriptional program in Slan+ non-classical monocytes

Immune complexes (ICs) play a central role in autoimmune diseases, where they accumulate in tissues, activate Fc gamma receptor-expressing cells, and promote chronic inflammation. However, the role of ICs as directional migratory cues for human leukocytes remains poorly defined. Here, we identify pro-inflammatory Slan + non-classical monocytes (SlanMo), a CD14 dim CD16 ++ monocyte subset, as the only blood leukocyte population that migrates directionally toward ICs. Using in vitro transmigration assays, we demonstrate that SlanMo respond to ICs in a concentration-dependent, gradient-dependent, and CD16-mediated manner. Strikingly, SlanMo follow IC gradients with high specificity, enabling their active and directed migration towards high concentrations of ICs. This migration is independent of G protein-coupled receptor signaling, and is, therefore, not dependent on chemokines. Guided by our phosphoproteomic analysis of migrating SlanMo, we identified ROCK, Lyn, crk, FAK, and moesin as relevant signaling proteins. Our transcriptomic profiling of SlanMo after migration on immobilized ICs versus uncoated surfaces revealed enrichment of pathways linked to SLE as well as an upregulation of genes associated with antigen processing, endocytosis, and protein digestion. These findings suggest that ICs can act as directional cues for selective leukocyte recruitment of pro-inflammatory SlanMo which may be of relevance in IC-rich environments such as in SLE.