The Sema3E/PlexinD1 axis has been shown to regulate immune responses, especially in allergic inflammation and macrophage cytokine production. Previous studies have shown that this axis is required for immune homeostasis and its disruption can worsen inflammatory responses, as seen in lung interstitial macrophages (IMs). Sex differences in innate immunity, including macrophages, are well established, with males being more pro-inflammatory and females being more anti-inflammatory. This sex difference can impact how immune cells, regulate cytokine production, including IL-10, a key anti-inflammatory cytokine. My thesis focuses on the role of Sema3E/PlexinD1 in modulating IL-10 and TNF in macrophages, with an emphasis on sex differences and receptor dynamics, particularly TLR4 and CD14. The main hypothesis of this work is that deletion of Sema3E/PlexinD1 changes IL-10 production in response to LPS in a sex-dependent manner, leading to different inflammatory outcomes in males and females. To test this, the project used an HDM model of allergic asthma in vivo and measured cytokines in bone marrow-derived macrophages (BMDMs) in vitro, following TLR4 activation. BMDMs were challenged with 100 ng/ml of LPS and cytokine protein levels were measured by ELISA. Flow cytometry was used to analyze TLR4 and CD14 internalization dynamics. Sema3E-Fc was added before LPS stimulation to see if cytokine production and receptor dynamics could be restored. The results showed sex-specific cytokine production in Sema3E KO BMDMs. Males produced more IL-10, while females produced more TNF. PlexinD1 KO BMDMs displayed an early increase in TNF production shortly after LPS stimulation, indicative of an immediate pro-inflammatory response. This was followed by a delayed increase in IL-10 levels, a key anti-inflammatory cytokine, at later times. This sequential pattern suggests a counter-regulatory mechanism where the initial pro-inflammatory TNF response triggers a subsequent rise in IL-10 to limit inflammation and promote resolution of the immune response. Sema3E-Fc restored cytokine profiles in a sex-dependent manner. In female BMDMs, Sema3E-Fc treatment decreased TNF and increased IL-10 levels, whereas in male BMDMs, it increased TNF and decreased IL-10 levels. This highlights the importance of Sema3E’s role in modulating inflammation differently between sexes, further highlighting its regulatory function in immune responses. Sema3E KO disrupted TLR4 and CD14 receptor dynamics, with an inverse correlation in WT BMDMs and a positive correlation in Sema3E KO BMDMs. Sema3E KO and PlexinD1 KO BMDMs secreted IL-1β after LPS stimulation, suggesting NLRP3 inflammasome activation. This was sex-dependent, with Sema3E enhancing IL-1β secretion in males and decreasing it in females. Overall, this demonstrates the complex role of Sema3E in macrophage polarization, cytokine production, and inflammasome activation, and that there are sex differences in immune responses.