Semaphorin 3E deficiency impairs dendritic cell migration during chlamydial infection

Introduction: Dendritic cells (DCs) are essential sentinels linking innate and adaptive immunity, and their ability to migrate to secondary lymphoid organs is critical for mounting effective immune responses. Semaphorins are guidance molecules that regulate cell migration and immune function. Semaphorin 3E (Sema3E) and its receptor PlexinD1 play important roles in immune cell trafficking, but their specific functions in dendritic cell migration during microbial infection remain unclear. Materials and methods: Bone marrow-derived dendritic cells (BMDCs) were generated from wild-type (WT) and Sema3E knockout (Sema3E KO) mice. DC migration was assessed using a Transwell migration assay in response to CCL19 and CCL21 chemokines. Signaling mechanisms were investigated by analyzing Rac1 guanosine triphosphate (GTP), F-actin polymerization, and phosphorylation of extracellular signal-regulated kinase (Erk) and protein kinase B (Akt). The impact of Sema3E deficiency was examined in the context of Chlamydia muridarum infection. Results: Sema3E-deficient DCs infected with C. muridarum displayed impaired responses to chemokines CCL19 and CCL21 in vitro and reduced migration to lymph nodes in vivo. Sema3E-deficient mice exhibited decreased numbers of lung and spleen DCs after chlamydial infection, with lower CD103+ lung DC and CD8α+ spleen DC counts. Mechanistically, Sema3E-deficient C. muridarum-infected DCs demonstrated decreased Rac1 GTP activity, F-actin polymerization, and phosphorylation of Erk and Akt, key signaling pathways for DC migration upon CCL19 stimulation. Conclusions: These findings reveal that Sema3E is essential for dendritic cell migration by regulating Rac1-mediated cytoskeletal dynamics and key signaling pathways. This work identifies Sema3E as a novel modulator of DC trafficking with therapeutic potential for enhancing anti-microbial immunity.