Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum.

The innate immune system has evolved the capacity to detect specific pathogens and to interrogate cell and tissue integrity in order to mount an appropriate immune response. Loss of homeostasis in the endoplasmic reticulum (ER) triggers the ER-stress response, a hallmark of many inflammatory and infectious diseases. The IRE1/XBP1 branch of the ER-stress signaling pathway has been recently shown to regulate and be regulated by innate immune signaling pathways in both the presence and absence of ER-stress. By contrast, innate immune pathways negatively affect the activation of two other branches of the ER-stress response as evidenced by reduced expression of the pro-apoptotic transcription factor CHOP. Here we will discuss how innate immune pathways and ER-signaling intersect to regulate the intensity and duration of innate immune responses

Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization

SummaryObjectiveTo investigate the in vivo role of the IRE1/XBP1 unfolded protein response (UPR) signaling pathway in cartilage.DesignXbp1flox/flox.Col2a1-Cre mice (Xbp1CartΔEx2), in which XBP1 activity is ablated specifically from cartilage, were analyzed histomorphometrically by Alizarin red/Alcian blue skeletal preparations and X-rays to examine overall bone growth, histological stains to measure growth plate zone length, chondrocyte organization, and mineralization, and immunofluorescence for collagen II, collagen X, and IHH. Bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were used to measure chondrocyte proliferation and cell death, respectively. Chondrocyte cultures and microdissected growth plate zones were analyzed for expression profiling of chondrocyte proliferation or endoplasmic reticulum (ER) stress markers by Quantitative PCR (qPCR), and of Xbp1 mRNA splicing by RT-PCR to monitor IRE1 activation.ResultsXbp1CartΔEx2 displayed a chondrodysplasia involving dysregulated chondrocyte proliferation, growth plate hypertrophic zone shortening, and IRE1 hyperactivation in chondrocytes. Deposition of collagens II and X in the Xbp1CartΔEx2 growth plate cartilage indicated that XBP1 is not required for matrix protein deposition or chondrocyte hypertrophy. Analyses of mid-gestation long bones revealed delayed ossification in Xbp1CartΔEx2 embryos. The rate of chondrocyte cell death was not significantly altered, and only minimal alterations in the expression of key markers of chondrocyte proliferation were observed in the Xbp1CartΔEx2 growth plate. IRE1 hyperactivation occurred in Xbp1CartΔEx2 chondrocytes but was not sufficient to induce regulated IRE1-dependent decay (RIDD) or a classical UPR.ConclusionOur work suggests roles for XBP1 in regulating chondrocyte proliferation and the timing of mineralization during endochondral ossification, findings which have implications for both skeletal development and disease

Protective role of nuclear factor of activated T cells 2 in CD8+ long-lived memory T cells in an allergy model.

BACKGROUND: The transcriptional regulation of cytokines released and controlled by memory T cells is not well understood. Defective IFN-gamma production in allergic asthma correlates in human beings with the risk of wheezing in childhood. OBJECTIVE: To understand the role of the transcription factor nuclear factor of activated T cells 2 (NFATc2) in memory and effector T cells in the airways in experimental allergic asthma. METHODS: We used murine models of allergic asthma and adoptive cell transfer of fluorescence-activated sorted cells in a disease model. RESULTS: Mice lacking NFATc2 developed an increase in airwayhyperresponsiveness (AHR), remodeling, and serum IgE levelson ovalbumin sensitization. This phenotype was associated withCD81CD1222 T cells deficient in IFN-g production in theairways. The origin of this phenotype in NFATc2(2/2) mice wasrelated to an expanded population of lung CD81CD1221(IL-2Rb chain) CD127hi (IL-7 receptor [R] a chain1) long-livedmemory cells. Adoptive transfer of ovalbumin-specific CD81NFATc2(2/2) T cells enhanced the AHR generated byNFATc2(2/2) CD41 T cells in immunodeficient mice, increasedIL-17, and reduced IFN-g production in the reconstituted mice.Depletion of the memory CD81CD1221IL-7Rhigh T-cellpopulation corrected the defect in IFN-g production by lungNFATc2(2/2) CD81CD1222 cells and abrogated the increasedAHR observed in NFATc2(2/2) CD81 T-cell-reconstituted micewith a severe combined immunodeficiency disorder. CONCLUSION: Taken together, our results suggest that NFATc2 expression in long-lived memory CD8+ T cells controls IL-2 and IFN-gamma production in lung CD8+ T cells, which then limits TH17 and TH2 development in the airways during allergen challenge