Expression of a constitutively active p38α mutant in mice causes early death, anemia, and accumulation of immunosuppressive cells

• Published in: The FEBS journal Vol. 288; no. 13; pp. 3978 - 3999
• Main Authors: Darlyuk‐Saadon, Ilona, Heng, Chew Kiat Matthew, Bai, Chen, Gilad, Nechama, Yu, Wei‐Ping, Meng Huang Mok, Michelle, Wong, W.S. Fred, Engelberg, David
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2021
• Subjects: Abnormalities; Accumulation; active variants; Aging; Allergies; Anemia; Anemia - enzymology; Anemia - genetics; Animals; Blood; Blood tests; Body weight; Body Weight - genetics; Bone marrow; Bronchus; Cytokines - blood; Cytokines - metabolism; Eukaryotes; Feedback inhibition; Flow cytometry; Gene Expression Regulation, Enzymologic; Hematopoietic stem cells; Hemolytic anemia; immunosuppressive cells; Inflammatory diseases; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Lungs; Macrophages; Macrophages - classification; Macrophages - immunology; Macrophages - metabolism; MAP kinase; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitogen-Activated Protein Kinase 14 - genetics; Mitogen-Activated Protein Kinase 14 - metabolism; Mutation; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; p38α; Phenotypes; Protein kinase; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Stem cell transplantation; Stem cells; Substrate Specificity; Substrates; Suppressor cells; Transgenic mice; transgenic mouse; immunosuppressive cells; active variants; transgenic mouse; anemia; p38α
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.15697

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. Elevated expression of the MAP kinase p38α is known to be associated with chronic inflammation; however, it is unclear whether its constitutive activity is a driver or consequence of pathology. This is due to the lack of a tool for specific activation of p38α in vivo. Here, David Engelberg et al. address this challenge by developing a transgenic mouse model that allows inducible expression of an intrinsically active p38α variant. Upon p38α expression, mice develop anaemia, accumulation of immunosuppressive cells and early death, highlighting the severe whole‐body impact of p38α activation. With refinement, this model could be used to explore the mechanisms underlying p38α‐associated inflammation in vivo.