Overexpression of Dominant Negative Peroxisome Proliferator-Activated Receptor-γ (PPARγ) in Alveolar Type II Epithelial Cells Causes Inflammation and T-Cell Suppression in the Lung

Abstract

In previous work, we demonstrated that neutral lipids are essential to maintaining alveolar homeostasis. Blockage of cholesteryl ester and triglyceride metabolism in the lysosomal acid lipase (LAL) knockout mouse model resulted in heterogeneous phenotypes in the lung, including hypercellularity and emphysema.

Airway epithelial cell PPARγ modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice

“…Furthermore, we have demonstrated that the mice used in this study do not display spontaneous, progressive airspace enlargement or emphysema (69). Consistent with our results, expression of a dominant-negative mutant form of PPAR␥ in the lung epithelium of mice results in chronic inflammation and airspace enlargement (88). The relevance of this dominant-negative model is not entirely clear, since deficiency in conditionally targeted mice does not result in chronic inflammation in the absence of a "second hit" such as continuous exposure to CS.…”

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

“…In this system, a previously established c-fms-rtTA-transgenic mouse line 9 and a (TetO) 7 -CMV-dnPPAR␥-transgenic mouse line 22 were crossbred. To assess the effect of overexpression of dnPPAR␥ on progenitor populations, the BM cells from c-fms-rtTA/(TetO) 7 -CMV-dnPPAR␥-bitransgenic mice treated with doxycycline for 3 months were analyzed for the percentage and total cell numbers of IL- 24 Overexpression of dnPPAR␥ resulted in significant increase in the percentages of LSK, LK, CMP, and GMP progenitors from doxycycline-treated bitransgenic mice compared with untreated mice (Figure 1).…”

“…The putative PPARE sites within the promoters of Api6, IL-1␤, IL-6, MMP12, and TNF-␣ were identified as described previously. 22 An anti-Flag polyclonal Ab was used to immunoprecipitate the dnPPAR␥-Flag/DNA complex. In doxycycline-treated mice, Flag-tagged dnPPAR␥ was detected bound to the promoters of the Api6, IL-1␤, IL-6, MMP12, and TNF-␣ genes by quantitative real-time PCR analysis ( Figure 3A).…”

“…We reported previously that overexpression of dnPPAR␥ in lung epithelial cells also promotes regional MDSC expansion, immune suppression, and emphysema in the lung. 22 Pathogenesis of LAL is a complex process involving multiple pathways and biologic events. In addition to the PPAR␥ pathway, other molecular pathways and mechanisms may also be involved in LAL function and remained to be identified in future studies.…”

Myeloid-specific expression of Stat3C results in conversion of bone marrow mesenchymal stem cells into alveolar type II epithelial cells in the lung

“…FACS analysis of CD11b, Gr-1, CD3 and B220 cells was the same as previously described [24,25]. FACS analysis of Stat3C-Flag fusion protein was analyzed by monoclonal ANTI-FLAG ® M2-FITC antibody (F4049; Sigma, Saint Louis, MI).…”