Tpl2 (MAP3K8) regulates the migration, differentiation, and function of critical innate immune cells during the inflammatory response
Rowley, Sean Michael
MetadataShow full item record
The protein kinase Tpl2 (MAP3K8) regulates innate inflammatory responses and is being actively pursued for therapeutic inhibition during chronic autoimmunity. Herein, we addressed the contribution of Tpl2 to pro-inflammatory responses of NK cells and macrophages. Despite the Tpl2-dependent regulation of IFNγ secretion by CD4+ T-cells, NK cell IFNγ production, STAT4 expression, and expression of cytotoxic machinery occurred independently of Tpl2. In contrast, tpl2-/- macrophages were functionally defective, as they displayed impaired chemokine and chemokine receptor expression following LPS stimulation and were defective in migrating in vivo to inflamed tissues. Tpl2-/- macrophages were also impaired in their differentiation towards a pro-inflammatory phenotype (M1) while conversely displaying an enhanced anti-inflammatory phenotype (M2). Overall, this work provides additional support for targeting Tpl2, through its effects on macrophage recruitment and differentiation, for the treatment of autoimmunity.