Background
Candida albicans is the most common opportunistic human fungal pathogen. The chemokine ligand CXCL1 plays a protective role in fungal infection through the recruitment of neutrophils. TRAF1 (tumor necrosis factor-associated factor 1) can be highly induced by proinflammatory stimuli such as LPS and TNF and has been implicated in septic shock. However, the role of TRAF1 in infection, especially fungal infection, remains elusive. Herein, we reveal that TRAF1 suppresses the antifungal immune response to Candida albicans intradermal infection through the regulation of CXCL1 induction and neutrophil recruitment.
Conclusion
TRAF1-deficient mice can better control fungal infection in the skin, a process attributable to the CXCL-neutrophil axis. Mechanistically, TRAF1 likely regulates CXCL1 expression in both macrophages and keratinocytes through the transcriptional factor NFκB and STAT1, respectively. Our finding offers new insight into the understanding of the immune regulatory mechanisms in host defense against C. albicans infection.
Methods
A mouse model of C. albicans intradermal infection was established. The Traf1-/- mice and Traf1-/- immortalized human keratinocytes were generated. The p65 inhibitor triptolide, STAT1 inhibitor fludarabine, neutrophil-depletion antibody Ly6G, and neutralizing antibody for CXCL1 were utilized. The expression of proinflammatory cytokines and chemokines was assessed by real-time PCR and ELISA, and the activation of signaling molecules was analyzed by Western blotting. Hematoxylin and eosin staining and periodic acid Schiff staining were used for histology or fungal detection, respectively. The immunofluorescence and flow cytometry analyses were employed in the assessment of immune cell infiltration. Bone marrow transplantation and adoptive transfer experiments were conducted to establish a role for TRAF1 in the macrophage compartment in fungal skin infection.
Results
TRAF1-deficient mice demonstrated improved control of Candida albicans intradermal infection, and concomitant increase in neutrophil recruitment and reduction in fungal burden. The chemokine CXCL1 was upregulated in the TRAF1-deficient macrophages treated with heat-killed C. albicans. Mechanistically, TRAF1-deficient macrophages showed increased activation of transcription factor NFκB p65. The human CXCL8 was also highly induced in the TRAF1-deficient human keratinocytes upon TNF stimulation through decreasing the activation of transcription factor STAT1. TRAF1-deficient macrophages played a critical role in containing the C. albicans skin infection in vivo.