This study aims to elucidate the regulatory role of suppressor of cytokine signaling 3 (SOCS3) in macrophage polarization and its functional impact on host immune responses against Sporothrix globosainfection. As an important fungal pathogen causing sporotrichosis, S. globosamay evade host defenses by modulating immune signaling pathways. This research seeks to clarify whether SOCS3-mediated JAK-STAT signaling influences macrophage polarization and antifungal immunity during infection.

Using a THP-1-derived macrophage model, SOCS3 expression was modulated via lentiviral overexpression or siRNA knockdown. Macrophages were polarized into M1 (LPS+IFN-γ) or M2 (IL-4+IL-13) phenotypes and infected with S. globosa. Fungicidal activity was assessed by colony-forming unit (CFU) assays. Cytokine secretion (TNF-α, IL-6, IL-10, Arg-1) was evaluated via ELISA and qRT-PCR. SOCS3, p-JAK2, and p-STAT3 expression were analyzed using Western blot and protein microarrays. Statistical significance was determined using ANOVA and t-tests.

S. globosainfection downregulated SOCS3 expression and reduced JAK2/STAT3 phosphorylation, promoting M2 polarization and impairing antifungal immunity. SOCS3 knockdown enhanced M2 markers (IL-10, Arg-1) and increased fungal survival, whereas SOCS3 overexpression promoted M1 polarization (elevated TNF-α, IL-6) and strengthened antifungal responses. Protein microarray and pathway analysis confirmed significant involvement of JAK-STAT signaling in infection-induced immune modulation.

These results demonstrate that SOCS3 plays a pivotal role in regulating macrophage polarization through the JAK2-STAT3 signaling pathway during S. globosainfection. Downregulation of SOCS3 shifts the balance toward M2 polarization, facilitating immune evasion and fungal survival. Therefore, targeting SOCS3 may represent a promising therapeutic strategy to modulate immune responses and improve outcomes in sporotrichosis.