Role of IKK alpha in lymphoid organ development

Division Of Basic Sciences - Nci

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Abstract

We generated kinase-dead Ikka knock-in mice (KA/KA) carrying a lysine (K) to alanine (A) mutation at amino acid 44, an ATP binding site within the kinase domain of IKKa. KA/KA mice exhibit autoimmune responses in multiple organs, characterized by increased infiltration of CD4+ T cells, macrophages, and neutrophils as well as heightened susceptibility to fungal infection (Zhu et al and Hu Cell Host and Microbe 2017). C. albicans is associated with human autoimmune diseases, accompanied by reduced mTEC numbers and diminished AIRE expression; however, this fungus is not found in mice. In addition, C. albicans infection induces IL-17A expression. Many studies have shown that increased IL-17A promotes tumorigenesis. To evaluate the role of C. albicans and IL-17A in carcinogenesis, we orally infected KA/KA, KA/KA;Il17a-/-, and WT mice with C. albicans. Approximately 10% of KA/KA mice develop spontaneous esophageal squamous cell carcinoma (ESCC). Oral C. albicans infection enhanced the ESCC incidence from 10% to 90% in KA/KA mice. Following C. albicans infection, KA/KA;Il17a-/- mice showed increased fungal infection, died earlier, and exhibited the similar ESCC incidence compared to KA/KA mice, suggesting that fungus-enhanced tumorigenesis undergo the pathway differing from IL-17A-promoting tumor pathway. Currently, we are investigating the underlying mechanism by which C. albicans infection promotes ESCC development and the innate immune cells contribute to fungus-infection tumorigenesis.