Tissue factor binds to and inhibits interferon-α receptor 1 signaling.

Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.

Longitudinal changes in brain-derived neurotrophic factor (BDNF) but not cytokines contribute to hippocampal recovery in anorexia nervosa above increases in body mass index.

BACKGROUND: Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. METHODS: Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. RESULTS: Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). CONCLUSIONS: These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.

Effect of serum concentrations of IL-6 and TNF-α on brain structure in anorexia nervosa: a combined cross-sectional and longitudinal study.

Previous studies of brain structure in anorexia nervosa (AN) have reported reduced gray matter in underweight patients, which largely normalizes upon weight gain. One underlying biological mechanism may be glial cell alterations related to low-grade inflammation. Here, we investigated relationships between brain structure as measured by magnetic resonance imaging and serum concentrations of two pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) cross-sectionally in 82 underweight adolescent and young adult female patients (mean age 16.8 years; 59 of whom were observed longitudinally after short-term weight restoration; mean duration 2.8 months), 20 individuals long-term weight-recovered from AN (mean age 22.7 years) and 105 healthy control (HC) participants (mean age 17.2 years). We measured cortical thickness, subcortical volumes and local gyrification index, a measure of cortical folding. In contrast to most previous studies of cytokine concentrations in AN, we found no cross-sectional group differences (interleukin-6: p = 0.193, tumor necrosis factor alpha: p = 0.057) or longitudinal changes following weight restoration (interleukin-6: p = 0.201, tumor necrosis factor alpha: p = 0.772). As expected, widespread gray matter reductions (cortical thickness, subcortical volumes, cortical folding) were observed in underweight patients with AN compared to HC. However, we found no evidence of associations between cytokine concentrations and structural brain measures in any participant group. Furthermore, longitudinal changes in cytokine concentrations were unrelated to changes in gray matter. In conclusion, we did not identify any association between (sub-)inflammatory processes and structural brain changes in AN. Future studies are needed to elucidate which other factors besides nutritional status may contribute to brain morphological alterations.