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Abstract
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 IFN secretion by CD4+ T-cells, NK cell IFN 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.