Data that underlies this paper.

Background
Sporotrichosis is a subcutaneous mycosis caused by members of the genus Sporothrix, among which Sporothrix globosa (S. globosa) is the predominant etiological agent in Asia. T cell immunity plays crucial roles in fungal infections, yet the local T cell immune profile in sporotrichosis lesions remains unclear. IL-18, a pleiotropic cytokine capable of modulating T cell responses, is also poorly understood in host defense against S. globosa.
Methodology/principal findings
qPCR, western blot, and IHC/mIHC were employed to profile IL-18, IL-18 BP, caspase-1 and IL-18R axis, along with Th1,Th2, and Th17 cells and their specific cytokines in sporotrichosis lesions versus healthy skin. Cellular sources of IL-18 in the lesions were identified via mIHC, and IL-18 production from keratinocyte/PBMCs exposed to S. globosa in vitro was tested by qPCR and western blot. Flow cytometry was performed to evaluate the role of IL-18 in Th2 polarization in the PBMCs-S. globosa coculture system. Lesional skin exhibited hyperactivated IL-18 signaling, marked by upregulated IL-18, caspase-1, and IL-18R, alongside decreased IL-18 BP. IL-18 was primarily released by dermal dendritic cells and Langerhans cells, rather than keratinocytes. A mixed Th1/Th2/Th17 microenvironment with Th2 predominance correlated strongly with prolonged disease duration. Strikingly, IL-18 synergistically interacted with Th1-derived IL-2 to establish a self-reinforcing Th2 loop, as evidenced by the strong correlation between lesional IL-4 and IL-18 levels (r = 0.70) and the concomitant upregulation of IL-18/IL-2 during S. globosa-induced Th2 expansion in PBMCs—an effect reversed by IL-18/IL-2 neutralizing antibodies. Critically, this Th2 skewing was mechanistically dependent on NF-κB signaling, as demonstrated through pharmacological pathway inhibition.
Conclusions/significance
This study unveils the dual role of IL-18 in human sporotrichosis caused by S. globosa—amplifying both Th1 and Th2 responses but ultimately driving pathogenic Th2 polarization through IL-2 crosstalk. Our work identifies IL-18/IL-2/NF-κB axis as a key Th2-polarizing mechanism driving chronicity in this disease. Targeting this axis could recalibrate anti-fungal immunity, offering translational strategies for this subcutaneous disease.