Deaths from viral hepatitis continue to rise around the world due to the lack of early biomarkers. We aimed here to evaluate the chemokine CXCL14, as a novel biomarker in acute viral hepatitis. We used a mouse model of acute hepatitis induced by murine hepatitis virus (MHV), a hepatotropic and lytic coronavirus, and showed that CXCL14 is overexpressed in the liver and sera of infected mice. Using primary cultures of murine and human hepatocytes, we showed that hepatocytes are the main source of CXCL14 after lytic hepatotropic virus infection and that CXCL14 expression is also induced by the pro-inflammatory cytokines IL-6 and TNFα. CXCL14 KO mice infected with MHV were partially protected and showed an attenuated antiviral immune response compared to wild-type mice. Finally, we show that CXCL14 is overexpressed in the sera of human patients infected with hepatitis viruses A, B, and E or herpes simplex virus. A positive correlation between CXCL14 and ALT levels in the sera of patients with acute herpetic hepatitis, as well as in mice models, suggests that hepatocyte lysis is necessary for the release of CXCL14. Overall, these data highlight that CXCL14 expression is associated with the occurrence of acute viral hepatitis and could be considered an alarmin and a new indicator of inflammation. CXCL14 serum levels are also associated with the severity of viral-induced liver injury.
© 2025 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Lung tissue resident memory (TRM) cells are thought to play crucial roles in lung host defense. We have recently shown that immunization with the adjuvant LTA1 (derived from the A1 domain of E. coli heat labile toxin) admixed with OmpX from K. pneumoniae can elicit antigen specific lung Th17 TRM cells that provide serotype independent immunity to members of the Enterobacteriaceae family. However, the upstream requirements to generate these cells are unclear. Single-cell RNA-seq showed that vaccine-elicited Th17 TRM cells expressed high levels of IL-1R1, suggesting that IL-1 family members may be critical to generate these cells. Using a combination of genetic and antibody neutralization approaches, we show that Th17 TRM cells can be generated independent of caspase-1 but are compromised when IL-1α is neutralized. Moreover IL-1α could serve as a molecular adjuvant to generate lung Th17 TRM cells independent of LTA1. Taken together, these data suggest that IL-1α plays a major role in vaccine-mediated lung Th17 TRM generation.
© 2024. The Author(s).

Background: Alzheimer's Disease (AD) is a neuropathological condition marked by cognitive deterioration and chronic neuroinflammation. Previous investigations have unveiled a strong correlation between the gut microbiota and the progression of AD. In this study, our objective is to probe the effects of Parabacteroides distasonis ( P.distasonis ), previously found to be conspicuously diminished in AD patients, on the APP/PS1 mice model. Methods: : To assess the impact of orally administered P.distasonis on gut microbiota and metabolites, we utilized 16s rDNA sequencing and GC-MS to analyze gut composition and short-chain fatty acids in APP/PS1 mice after one month of P.distasonis gavage. To investigate the effects of P.distasonis administration over a six-month period on APP/PS1 mice, we evaluated cognitive function using novel object recognition and Y-maze tests, assessed intestinal barrier integrity and AD-related pathological features with immunofluorescence, and analyzed immune cell subpopulations in intestine, blood, spleen, and brain tissues via flow cytometry. The Luminex assay was employed to detect inflammatory cytokine secretion in the same regions. Results: : One-month oral administration of P.distasonis modulated the gut microbiota, elevated butyrate levels. Six-month oral administration of P.distasonis improved cognitive function in APP/PS1 mice, reducing Aβ deposition and inhibiting glial cell proliferation. It also amplified Treg cells within the gut, concomitant with the decreased Th1 proliferation and intestinal inflammation. Additionally, we observed the migration of peripheral CD4 + T cells to the brain through chemotaxis, accompanied by an increase in Treg cells and higher levels of anti-inflammatory factors such as IL-10 and TGF-β in the brain. Collectively, these multifaceted effects contributed to the alleviation of neuroinflammation. Conclusion: These findings underscore the potential of transplanting P.distasonis in alleviating AD-related pathology, suggesting a role for gut microbiota in neuroinflammation attenuation.

The efficacy of immune checkpoint inhibitors such as programmed cell death ligand 1 (PD-L1) antibodies in non-small cell lung cancer (NSCLC) is limited, and combined use with other therapies is recommended. Dipeptidyl peptidase 4 (DPP4) inhibitors, a class of small molecule inhibitors, are highly effective for treating type 2 diabetes. Emerging evidence implicates DPP4 inhibitors as immunomodulators that modify aspects of innate and adaptive immunity. We evaluated the combination of a DPP4 inhibitor (anagliptin) and PD-L1 blockade in an NSCLC mouse model.
The effect of the combination of anti-PD-L1 and anagliptin was evaluated in subcutaneous mouse models of NSCLC. Tumor-infiltrating immune cells were analyzed by flow cytometry. Bone marrow-derived monocytes of C57BL/6 mice were isolated in vitro to examine the underlying mechanism of anagliptin on the differentiation and polarization of macrophage.
Anagliptin dramatically improved the efficacy of PD-L1 antibody monotherapy by inhibiting macrophage formation and M2 polarization in the tumor microenvironment. Mechanistically, anagliptin suppressed the production of reactive oxygen species in bone marrow monocytes by inhibiting NOX1 and NOX2 expression induced by macrophage colony-stimulating factor, reduced late ERK signaling pathway activation, and inhibited monocyte-macrophage differentiation. However, the inhibitory effect was reactivated by lipopolysaccharide and interferon-gamma interacting with corresponding receptors during M1 macrophage polarization, but not M2.
Anagliptin can enhance PD-L1 blockade efficacy in NSCLC by inhibiting macrophage differentiation and M2 macrophage polarization, and combination therapy may be a promising strategy for treating PD-L1 blockade therapy-resistant patients with NSCLC.
© 2023. The Author(s).

Human endogenous retrovirus type W (HERV-W) is expressed in various cancers. We previously developed an adenovirus-vectored cancer vaccine targeting HERV-W by encoding an assembled HERV-W group-specific antigen sequence and the HERV-W envelope sequence Syncytin-1. Syncytin-1 is constitutively fusogenic and forms large multinucleated cell fusions when overexpressed. Consequently, immunising humans with a vaccine encoding Syncytin-1 can lead to the formation of extensive syncytia, which is undesirable and poses a potential safety issue. Here, we show experiments in cell lines that restoring an evolutionary lost cleavage site of the fusion inhibitory R-peptide of Syncytin-1 inhibit cell fusion. Interestingly, this modification of the HERV-W vaccine's fusogenicity increased the expression of the vaccine antigens in vitro. It also enhanced Syncytin-1-specific antibody responses and CD8+-mediated T-cell responses compared to the wildtype vaccine in vaccinated mice, with a notable enhancement in responses to subdominant T-cell epitopes but equal responses to dominant epitopes and similar rates of survival following a tumour challenge. The impairment of cell-cell fusion and the enhanced immunogenicity profile of this HERV-W vaccine strengthens the prospects of obtaining a meaningful immune response against HERV-W in patients with HERV-W-overexpressing cancers.