Activated Ets2 is required for persistent inflammatory responses in the motheaten viable model

The Ets2 transcription factor is constitutively phosphorylated on residue Thr⁷² in macrophages derived from mice homozygous for the motheaten viable (me-v) allele of the hemopoietic cell phosphatase (Hcph) gene. To genetically test the importance of signaling through residue Thr⁷² of Ets2 during inflammation, the Ets2^A72 mutant allele, which cannot be phosphorylated on Thr⁷², was combined with the Hcph^me-v allele in mice. Ets2^A72/A72 moderated the inflammation-related pathology of Hcph^me-v/me-v mice, as demonstrated by the increased life span and the decreased macrophage infiltration in skin and lungs of these mice. Macrophage apoptosis induced by cytokine withdrawal was also increased in the double-mutant mice. Importantly, the Ets2^A72/A72 allele resulted in decreased expression of inflammatory response genes, including TNF-α, CCL3, matrix metalloprotease 9, integrin α_M, and Bcl-X in alveolar macrophage. Ets2 phosphorylation was required for persistent activation of TNF-α following LPS stimulation of bone marrow-derived macrophages. The phosphorylation of Ets2 functions in the severe inflammatory phenotype of the me-v model by mediating both macrophage survival and inflammatory gene expression.