Tumor Progression Locus 2 (Tpl2) Kinase Promotes Chemokine Receptor Expression and Macrophage Migration during Acute Inflammation

• Published in: The Journal of biological chemistry 2014-05, Vol.289 (22), p.15788-15797
• Main Authors: Rowley, Sean M., Kuriakose, Teneema, Dockery, Lee M., Tran-Ngyuen, Thi, Gingerich, Aaron D., Wei, Lai, Watford, Wendy T.
• Format: Article
• Language: English
• Subjects: Acute Disease; Adaptor Proteins, Vesicular Transport - genetics; Animals; Autoimmunity; Cell Movement - immunology; Chemokines; Chemokines - immunology; Chemokines - metabolism; Female; Immunology; Inflammation; Inflammation - immunology; Lipopolysaccharide (LPS); Lipopolysaccharides - pharmacology; Macrophages; Macrophages - cytology; Macrophages - immunology; Male; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - immunology; MAP Kinase Kinase Kinases - metabolism; MAP Kinase Signaling System - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88 - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - immunology; Proto-Oncogene Proteins - metabolism; Receptors, CCR1 - genetics; Receptors, CCR1 - immunology; Receptors, CCR1 - metabolism; Receptors, CCR2 - genetics; Receptors, CCR2 - immunology; Receptors, CCR2 - metabolism; Receptors, CCR5 - genetics; Receptors, CCR5 - immunology; Receptors, CCR5 - metabolism; Receptors, Chemokine - genetics; Receptors, Chemokine - immunology; Receptors, Chemokine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.559344

In autoimmune diseases, the accumulation of activated leukocytes correlates with inflammation and disease progression, and, therefore, the disruption of leukocyte trafficking is an active area of research. The serine/threonine protein kinase Tpl2 (MAP3K8) regulates leukocyte inflammatory responses and is also being investigated for therapeutic inhibition during autoimmunity. Here we addressed the contribution of Tpl2 to the regulation of macrophage chemokine receptor expression and migration in vivo using a mouse model of Tpl2 ablation. LPS stimulation of bone marrow-derived macrophages induced early CCR1 chemokine receptor expression but repressed CCR2 and CCR5 expression. Notably, early induction of CCR1 expression by LPS was dependent upon a signaling pathway involving Tpl2, PI3K, and ERK. On the contrary, Tpl2 was required to maintain the basal expression of CCR2 and CCR5 as well as to stabilize CCR5 mRNA expression. Consistent with impairments in chemokine receptor expression, tpl2−/− macrophages were defective in trafficking to the peritoneal cavity following thioglycollate-induced inflammation. Overall, this study demonstrates a Tpl2-dependent mechanism for macrophage expression of select chemokine receptors and provides further insight into how Tpl2 inhibition may be used therapeutically to disrupt inflammatory networks in vivo. The accumulation of activated leukocytes correlates with autoimmunity and is regulated by chemokines. Tpl2-deficient macrophages display impaired chemokine receptor expression and migration under inflammatory conditions. Tpl2 promotes the induction and maintenance of macrophage chemokine receptor expression and cellular migration in vivo. Tpl2 inhibition may represent a treatment for autoimmune disorders by modulating chemokine receptor expression and preventing local accumulation of activated macrophages.