Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is an anti-inflammatory molecule. To study its biologic function in myeloid cells, dominant-negative PPAR gamma (dnPPAR gamma) was overexpressed in a myeloid-specific bitransgenic mouse model. In this bitransgenic system, overexpression of the dnPPAR gamma-Flag fusion protein in myeloidlineage cells abnormally elevated frequencies and total numbers of IL-7R alpha(-) Lin(-)c-Kit(+)Sca-1(-), Lin(-)/Scal(+)/c-Kit(+), common myeloid, and granulocyte-monocyte progenitor populations in the BM. dnPPAR gamma overexpression led to up-regulation of IL-1 beta, IL-6, and TNF alpha in the blood plasma. As a result, CD11b(+) Ly6G(+) cells were systemically increased in association with activation of Stat3, NF-kappa B, Erk1/2, and p38 molecules. Myeloid-derived suppressor cells (MDSCs) inhibited the proliferation and lymphokine production of wild-typeCD4(+) T cells in vitro. CD4(+) T cells from doxycyclinetreated bitransgenic mice displayed reduced proliferation and lymphokine release. Both CD4(+) and CD8(+) T-cell populations were decreased in doxycycline-treated bitransgenic mice. Multiple forms of carcinoma and sarcoma in the lung, liver, spleen, and lymph nodes were observed in doxycycline- treated bitransgenic mice. BM transplantation revealed that a myeloid-autonomous defect was responsible for MDSC expansion, immunosuppression, and tumorigenesis in these mice. These studies suggest that anti-inflammatory PPAR gamma in myeloid-lineage cells plays a key role in controlling pro-inflammatory cytokine synthesis, MDSCexpansion, immunosuppression, and the development of cancer. (Blood. 2012; 119(1): 115-126)