Sema3A Drives Alternative Macrophage Activation in the Resolution of Periodontitis via PI3K/AKT/mTOR Signaling

Macrophages actively participate in immunomodulatory processes throughout periodontal inflammation. Regulation of M1/M2 polarization affects macrophage chemokine and cytokine secretion, resulting in a distinct immunological status that influences prognosis. Semaphorin 3A (Sema3A), a neurite growth factor, exerts anti-inflammatory effects. In this study, we investigated the immunomodulation of Sema3A on macrophage-related immune responses in vivo and in vitro. Topical medications of Sema3A in mice with periodontitis alleviated inflammatory cell infiltration into gingival tissue and reduced areas with positive IL-6 and TNFα expression. We observed that the positive area with the M2 macrophage marker CD206 increased and that of the M1 macrophage marker iNOS decreased in Sema3A-treated mice. It has been postulated that Sema3A alleviates periodontitis by regulating alternative macrophage activation. To understand the mechanism underlying Sema3A modulation of macrophage polarization, an in vitro macrophage research model was established with RAW264.7 cells, and we demonstrated that Sema3A promotes LPS/IFNγ-induced M1 macrophages to polarize into M2 macrophages and activates the PI3K/AKT/mTOR signaling pathways. Inhibition of the PI3K signaling pathway activation might reduce anti-inflammatory activity and boost the expression of the inflammatory cytokines, iNOS, IL-12, TNFα, and IL-6. This study indicated that Sema3A might be a feasible drug to regulate alternative macrophage activation in the inflammatory response and thus alleviate periodontitis.