Immunity最新文献

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Systemic rotavirus (RV) infection poses a substantial health challenge in neonates, but the underlying pathogenesis remains elusive. In RV-infected neonatal mice and infants with biliary atresia (BA), we discovered that persistent type I interferon (IFN-I) signaling upregulated hepcidin expression in hepatocytes and TREM2⁺ macrophages. This impaired SLC40A1-mediated iron excretion, leading to lipid peroxidation- and ferroptosis-mediated tissue damage. In mice deficient in Slc40a1 in myeloid cells, iron accumulation promoted RV replication and IFN-I activation in Kupffer cells. Blocking IFN-I-hepcidin signaling and iron chelation reduced RV-induced tissue damage in mice. Folic acid suppressed IFN-I-hepcidin-iron signaling in mice, and in an open-label clinical trial, folic acid supplementation in infants with BA reduced cholangitis and liver transplantation rates. Our data show that hepcidin-iron dysregulation plays a critical role in neonatal RV infection and reveal therapeutic targets for BA and other RV-related neonatal diseases. The clinical trial was registered in the Chinese Clinical Trial Registry ChiCTR2100050992.

The meninges, located between the skull and brain, harbor immune cells that monitor the brain borders. Skull marrow communicates with the meninges via bone channels, enabling immune-cell trafficking, but little is known about bone channel formation and modulation. We found that bone channels were formed during the perinatal stage in mice, and we developed approaches to modulate them and assess their impact on meningeal immunity. Myeloid cell depletion with anti-colony-stimulating factor 1 receptor (αCSF1R) or targeted osteoclast inhibition with anti-receptor activator of nuclear factor kappa-B ligand (αRANKL) reduced channel size, whereas mechanoreceptor transient receptor potential vanilloid 4 (TRPV4)-driven bone remodeling enlarged them. Following channel manipulation, lymphocytic choriomeningitis virus (LCMV) infection showed reduced meningeal immune infiltration in αRANKL-treated mice and increased infiltration with TRPV4 activation. In an ex vivo skull assay, restricting channels impaired skull-derived immune-cell migration to the meninges, whereas enhancing remodeling promoted it. Our findings reveal that bone remodeling controls the skull-to-meninges axis and highlight its role in immune-cell migration into the meninges during neuroinflammation.

Enrichment of regulatory T (Treg) cells in solid organ cancers is generally associated with poor prognosis; however, colorectal cancer (CRC) stands out as a notable exception. Here, we examined the heterogeneity of tumoral Treg cells in CRC and identified two distinct tumoral Treg subsets with differential Il10 expression. Selective depletion of interleukin-10-expressing (IL-10⁺) Treg cells promoted tumor growth by lifting the restraint on IL-17 production from effector CD4⁺ T cells, thereby directly stimulating tumor cell proliferation; depletion of IL-10^- Treg cells led to pronounced tumor regression. In human CRC, IL-10⁺ and IL-10^- Treg abundance correlated with favorable and unfavorable prognosis, respectively. Accordingly, IL-10⁺ and IL-10^- Treg cells exhibited opposite enrichment patterns in adjacent normal colon tissues and tumors. Transcriptionally similar Treg subsets were observed across different human barrier tissue tumors. This functional dichotomy between Treg subsets may enable selective targeting of the pro-tumoral subset while preserving its anti-tumoral counterpart in CRC and other barrier tissue cancers.