| Semaphorin 7A is a glycosylphosphatidylinositol‑anchored, dimeric class‑7 semaphorin that resides on the outer leaflet of the plasma membrane and functions at the interface of the nervous and immune systems, where it acts both as a positive axon growth cue and as an immune semaphorin that modulates inflammatory responses through specific integrin and plexin receptors. The extracellular portion contains a sema domain with an RGD integrin‑interaction motif, followed by a PSI (plexin–semaphorin–integrin) domain and short juxtamembrane region linked to the membrane via a GPI anchor, and this arrangement allows Semaphorin 7A to form dimers and present multivalent binding surfaces to β1 integrins such as α1β1 and to plexin C1, creating distinct signaling platforms on neurons, endothelial cells and immune cells. In the nervous system, Semaphorin 7A promotes central and peripheral axon outgrowth rather than repulsion: addition of Sema7A enhances elongation and branching in a dose‑dependent manner, and genetic deletion leads to defects in olfactory tract development and axonal tract formation, with integrin engagement and downstream MAPK activation identified as the key mechanism by which Sema7A stimulates cytoskeletal reorganization and growth cone advance. In immunity, Sema7A is expressed on CD4⁺CD8⁺ thymocytes, activated T cells, monocytes, macrophages, microglia and endothelial cells, and acts as a potent immunomodulator; Sema7A on activated T cells stimulates cytokine production in monocytes and macrophages through α1β1 integrin at immunological synapses and is critical for the effector phase of T‑cell‑mediated inflammatory responses, with Sema7A‑deficient mice showing defective contact hypersensitivity and experimental autoimmune encephalomyelitis despite normal development and migration of effector T cells to challenged sites. In contrast, other work demonstrates that Sema7A can negatively regulate T‑cell activation, where deficiency leads to defective TCR down‑modulation, T‑cell hyperresponsiveness and more aggressive autoimmune disease, indicating that Sema7A has dual roles that depend on cellular context and receptor engagement, limiting autoimmune responses while promoting effector cytokine output at sites of inflammation. Sema7A also contributes to innate immune regulation: endothelial Sema7A promotes neutrophil migration under hypoxia and coordinates neutrophil responses in pulmonary inflammation and sepsis, and Sema7A on NK cells modulates cytokine‑induced memory‑like responses, placing this molecule as a shared guidance and activation cue across adaptive and innate compartments. In tissue remodeling and fibrosis, Sema7A is induced by TGF‑β1 in lung macrophages and endothelial cells and is required for TGF‑β1‑induced pulmonary fibrosis, acting via plexin C1 and β1 integrin to drive collagen deposition, endothelial permeability and inflammatory cell infiltration in models of lung disease and Kawasaki vasculitis. Autoimmune and inflammatory diseases such as rheumatoid arthritis and multiple sclerosis display elevated soluble and membrane Sema7A, generated in part by ADAM17‑mediated shedding, and blocking β1 integrin or Sema7A itself attenuates disease in experimental arthritis, underscoring its contribution to Th1/Th17 cytokine production, lymphangiogenesis and chronic inflammatory progression. In cancer, Sema7A is low or absent in normal breast tissue but re‑expressed or upregulated in involuting and tumor microenvironments, where increased expression correlates with poor prognosis and has been linked to epithelial–mesenchymal transition, tumor cell proliferation, migration, lung metastasis, angiogenesis and lymphangiogenesis through interactions with PLXNC1 and integrins, and Sema7A is now considered a candidate predictive and therapeutic target in several solid and hematologic malignancies. |
