Sporothrix schenckii regulates macrophage inflammatory responses via the c-JUN-induced Dab2 transcription

Area of Science:

• Immunology
• Molecular Biology
• Infectious Diseases

Background:

• Macrophages bridge innate and adaptive immunity, crucial in sporotrichosis.
• Sporothrix schenckii infection elicits macrophage polarization and inflammatory factor secretion.
• DAB2's role in sporotrichosis-induced inflammation and macrophage polarization remains unclear.

Purpose of the Study:

• To investigate DAB2 expression and its regulation of inflammatory factors during Sporothrix schenckii infection.
• To elucidate the molecular mechanisms underlying DAB2's function in sporotrichosis.

Main Methods:

• Examined DAB2 expression in BMDMs (Bone Marrow-Derived Macrophages) infected with Sporothrix schenckii.
• Utilized gene knockout models (Dab2 deficiency) to assess cytokine changes.
• Employed chromatin immunoprecipitation and luciferase reporter assays to identify transcription factors.
• Investigated JNK/c-JUN pathway activity in vitro and in an in vivo mouse model of sporotrichosis.

Main Results:

• Sporothrix schenckii infection upregulated DAB2 expression and induced a mixed M1/M2 macrophage phenotype.
• Cytokine profiles showed inhibition of IL-6, IL-1β, and Arg-1, with induction of TNF-α, IL-10, and MGL-1.
• Dab2 gene deficiency abrogated infection-induced cytokine alterations.
• Sporothrix schenckii infection inhibited JNK activity and increased c-JUN expression, with c-JUN identified as a transcriptional activator of DAB2.
• In vivo findings mirrored in vitro results, showing c-JUN upregulation and JNK inhibition in skin lesions.

Conclusions:

• Sporothrix schenckii infection promotes DAB2 expression through the JNK/c-JUN pathway in early stages.
• DAB2 plays a critical role in controlling inflammatory factor expression during sporotrichosis.
• The JNK/c-JUN/DAB2 axis represents a key regulatory mechanism in the host's immune response to Sporothrix schenckii.