MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype.

Prominent changes in the gut microbiota (referred to as "dysbiosis") play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I-like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology.

Overexpression of the transcription factor Sp1 activates the OAS-RNAse L-RIG-I pathway.

Deregulated expression of oncogenes or transcription factors such as specificity protein 1 (Sp1) is observed in many human cancers and plays a role in tumor maintenance. Paradoxically in untransformed cells, Sp1 overexpression induces late apoptosis but the early intrinsic response is poorly characterized. In the present work, we studied increased Sp1 level consequences in untransformed cells and showed that it turns on an early innate immune transcriptome.

Invariant NKT cells suppress CD8(+) T-cell-mediated allergic contact dermatitis independently of regulatory CD4(+) T cells.

Invariant natural killer T (iNKT) cells expressing a CD1d-restricted invariant αβTCR have key regulatory roles in autoimmunity, pathogen immunity, and tumor surveillance, but their function in the control of allergic skin diseases remains poorly documented. Using a model of contact hypersensitivity (CHS) to the hapten DNFB, we show here that iNKT cell deficiency results in enhanced skin inflammation due to augmented hapten-specific IFN-γ-producing CD8(+) effectors in skin draining lymph nodes (dLNs) and their massive recruitment into the allergen-exposed skin. Adoptive transfer and antibody depletion experiments as well as in vitro studies revealed that iNKT cells (1) reduce the severity of CHS, even in presensitized mice, (2) require hapten presentation by CD1d(+) dendritic cells (DCs) to dampen skin inflammation, and (3) produce IL-4 and IL-13 after CD1d-dependent in vitro stimulation by hapten-loaded DCs only in the presence of IFN-γ released from activated CD8(+) effector T cells.

Estrogens repress PGC1-α expression in the uterus.

PGC-1α is a transcriptional coactivator that is highly involved in several aspects of regulation of metabolism, including mitochondrial biogenesis and activity. Using several in vivo models, we here report that the expression of PGC-1α is repressed by estrogens in the mouse specifically in the uterus. In the absence of estrogens, expression of PGC-1α target genes involved in mitochondrial activity is activated, but not mitochondrial biogenesis.

Absence of ERRalpha in female mice confers resistance to bone loss induced by age or estrogen-deficiency.

Background: ERRalpha is an orphan member of the nuclear hormone receptor superfamily, which acts as a transcription factor and is involved in various metabolic processes. ERRalpha is also highly expressed in ossification zones during mouse development as well as in human bones and cell lines. Previous data have shown that this receptor up-modulates the expression of osteopontin, which acts as an inhibitor of bone mineralization and whose absence results in resistance to ovariectomy-induced bone loss.

Modulating estrogen receptor-related receptor-alpha activity inhibits cell proliferation.

High expression of the estrogen receptor-related receptor (ERR)-alpha in human tumors is correlated to a poor prognosis, suggesting an involvement of the receptor in cell proliferation. In this study, we show that a synthetic compound (XCT790) that modulates the activity of ERRalpha reduces the proliferation of various cell lines and blocks the G(1)/S transition of the cell cycle in an ERRalpha-dependent manner. XCT790 induces, in a p53-independent manner, the expression of the cell cycle inhibitor p21(waf/cip)(1) at the protein, mRNA, and promoter level, leading to an accumulation of hypophosphorylated Rb.