| First Author | Darlyuk-Saadon I | Year | 2021 |
| Journal | FEBS J | Volume | 288 |
| Issue | 13 | Pages | 3978-3999 |
| PubMed ID | 33410203 | Mgi Jnum | J:329390 |
| Mgi Id | MGI:7344180 | Doi | 10.1111/febs.15697 |
| Citation | Darlyuk-Saadon I, et al. (2021) Expression of a constitutively active p38alpha mutant in mice causes early death, anemia, and accumulation of immunosuppressive cells. FEBS J 288(13):3978-3999 |
| abstractText | The MAP kinase p38alpha is associated with numerous processes in eukaryotes, and its elevated activity is a prominent feature of inflammatory diseases, allergies, and aging. Since p38alpha is a nodal component of a complex signaling network, it is difficult to reveal exactly how p38alpha contributes to disparate outcomes. Identification of p38alpha -specific effects requires activation of p38alpha per se in vivo. We generated a transgenic mouse model that meets this requirement by allowing inducible and reversible expression of an intrinsically active p38alpha molecule (p38alpha(D176A+F327S) ). p38alpha's activation across all murine tissues resulted in a significant loss of body weight and death of about 40% of the mice within 17 weeks of activation, although most tissues were unaffected. Flow cytometric analysis of the lungs and bronchoalveolar lavage fluid detected an accumulation of 'debris' within the airways, suggesting impaired clearance. It also revealed increased numbers of alternatively activated alveolar macrophages and myeloid-derived suppressor cells within the lung, pointing at suppression and resolution of inflammation. Blood count suggested that mice expressing p38alpha(D176A+F327S) suffer from hemolytic anemia. Flow cytometry of bone marrow revealed a reduced number of hematopoietic stem cells and abnormalities in the erythroid lineage. Unexpectedly, p38alpha's substrate MAPKAPK2, mitogen-activated protein kinase-activated protein kinase 2 was downregulated in mice expressing p38alpha(D176A+F327S) , suggesting that constitutive activity of p38alpha may impose pathological phenotypes by downregulating downstream components, perhaps via a feedback inhibition mechanism. In summary, this new mouse model shows that induced p38alpha activity per se is hazardous to mouse vitality and welfare, although pathological parameters are apparent only in blood count, bone marrow, and lungs. |
