Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been recognized to regulate adaptive immunity through Th17 differentiation, Treg functions, and TFH responses. However, its role in adaptive immunity and autoimmune disease is still not clear, possibly due to sexual differences. Here, we investigated in vitro treatment study with the PPARγ agonist pioglitazone to compare Th1, Th2, and Th17 differentiation in male and female mouse splenic T cells. Pioglitazone treatment significantly inhibited various effector T cell differentiations including Th1, Th2, and Th17 cells from female naïve T cells, but it selectively reduced IL-17 production in male Th17 differentiation. Interestingly, pioglitazone and estradiol (E2) co-treatment of T cells in males inhibited differentiation of Th1, Th2, and Th17 cells, suggesting a mechanism for the greater sensitivity of PPARγ to ligand treatment in the regulation of effector T cell differentiation in females. Collectively, these results demonstrate that PPARγ selectively inhibits Th17 differentiation only in male T cells and modulates Th1, Th2, and Th17 differentiation in female T cells based on different level of estrogen exposure. Accordingly, PPARγ could be an important immune regulator of sexual differences in adaptive immunity.

Sex Hormones in Acquired Immunity and Autoimmune Disease

“…PPARγ mediated inhibition of Th1, Th2, and Th17 differentiation of naïve CD4 T cells from female C57Bl/6 mice whereas male cells only showed Th17 inhibition. Estradiol co-treatment of male cells inhibited Th1, Th2, and Th17 differentiation indicating that estrogen increases the sensitivity of male cells to the effects of PPARγ activation ( 92 ). Administration of the neurosteroid dehydroepiandrosterone (DHEA) inhibited Th17 responses and induced IL-10 producing regulatory cells in EAE and importantly reversed established paralysis and central nervous system (CNS) inflammation in mice.…”

T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities

“…Although patients with HS do not seem to have increased levels of androgens, beneficial clinical responses have been reported with antiandrogens, such as cyproterone acetate, spironolactone and the 5α‐reductase inhibitor finasteride . Peroxisome proliferator‐activated receptor‐γ (PPARγ) regulates adaptive immunity through Th17 differentiation and Treg functions . PPARγ is a negative regulator of Th17 differentiation .…”

“…183,184 Peroxisome proliferator-activated receptor-c (PPARc) regulates adaptive immunity through Th17 differentiation and Treg functions. 185 PPARc is a negative regulator of Th17 differentiation. 186 PPARc mediates the inhibition of TGF-b/IL-6-induced expression of RORct in T cells.…”

Ozone autohemotherapy elevates PPAR-γ expression to lower blood lipid in treatment for psoriasis

“…Studies have confirmed that PPAR-γ plays a critical role in regulating Th17/Treg cell balance. PPAR-γ agonists inhibit the differentiation of Th17 cells while promoting Treg polarization, and suppress inflammatory responses by inducing the production of IL-10 and inhibiting the generation of IL-17a, IL-17f, IL-22, and IL-23 [25]. The mouse models experiment showed that activation of PPAR-γ action on Treg cells can alleviate inflammatory response and increased insulin sensitivity [26].…”