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

Ilona Darlyuk-Saadon, Chew Kiat Matthew Heng, Chen Bai, Nechama Gilad, Wei Ping Yu, Michelle Meng Huang Mok, W. S.Fred Wong, David Engelberg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3978-3999
Number of pages22
JournalFEBS Journal
Volume288
Issue number13
DOIs
StatePublished - Jul 2021

Keywords

  • active variants
  • anemia
  • immunosuppressive cells
  • p38α
  • transgenic mouse

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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