Expression of a constitutively active p38α mutant in mice causes early death, anemia, and accumulation of immunosuppressive cells.
Ilona Darlyuk-SaadonChew Kiat Matthew HengChen BaiNechama GiladWei-Ping YuMichelle Meng Huang MokW S Fred WongDavid EngelbergPublished in: The FEBS journal (2021)
The MAP kinase p38α is associated with numerous processes in eukaryotes, and its elevated activity is a prominent feature of inflammatory diseases, allergies, and aging. Since p38α is a nodal component of a complex signaling network, it is difficult to reveal exactly how p38α contributes to disparate outcomes. Identification of p38α -specific effects requires activation of p38α per se in vivo. We generated a transgenic mouse model that meets this requirement by allowing inducible and reversible expression of an intrinsically active p38α molecule (p38αD176A+F327S ). p38α'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 p38αD176A+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, p38α's substrate MAPKAPK2, mitogen-activated protein kinase-activated protein kinase 2 was downregulated in mice expressing p38αD176A+F327S , suggesting that constitutive activity of p38α may impose pathological phenotypes by downregulating downstream components, perhaps via a feedback inhibition mechanism. In summary, this new mouse model shows that induced p38α activity per se is hazardous to mouse vitality and welfare, although pathological parameters are apparent only in blood count, bone marrow, and lungs.
Keyphrases
- bone marrow
- mouse model
- stem cells
- high fat diet induced
- protein kinase
- induced apoptosis
- wild type
- body weight
- poor prognosis
- single cell
- oxidative stress
- flow cytometry
- mesenchymal stem cells
- gene expression
- chronic kidney disease
- cell cycle arrest
- type diabetes
- lymph node
- magnetic resonance imaging
- cystic fibrosis
- insulin resistance
- adipose tissue
- diabetic rats
- signaling pathway
- binding protein
- metabolic syndrome
- peripheral blood
- endoplasmic reticulum stress
- magnetic resonance
- machine learning
- single molecule
- drug induced
- skeletal muscle
- high density
- preterm birth