Transmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). We investigated wither STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice. Mice with disruption of Tmem173 (STING^gt) on a C57BL/6J background, mice without disruption of this gene (controls), and mice with disruption of Tmem173 only in myeloid cells were fed a standard chow diet, a high-fat diet (HFD, 60% fat calories), or a methionine- and choline-deficient diet (MCD). Liver tissues were collected and analyzed by histology and immunohistochemistry. Bone marrow cells were isolated from mice, differentiated into macrophages, and incubated with DMXAA (an activator of STING) or cGAMP. Macrophages or their media were applied to mouse hepatocytes or human hepatic stellate cells (LX2) cells, which were analyzed for cytokine expression, protein phosphorylation, and fat deposition (oil red O staining following incubation with palmitate). We obtained liver tissues from patients with and without NAFLD and analyzed these by immunohistochemistry. Non-parenchymal cells of liver tissues from patients with NAFLD had higher levels of STING than liver tissues from patients without NAFLD. STING^gt mice and mice with disruption only in myeloid cells developed less severe hepatic steatosis, inflammation, and/or fibrosis following a HFD or MCD than control mice. Levels of phosphorylated JNK and p65 and the mRNAs encoding TNF, IL1B, and IL6 (markers of inflammation) were significantly lower in liver tissues from STING^gt mice vs control mice after a HFD or MCD. Transplantation of bone marrow cells from control mice to STING^gt mice restored the severity of steatosis and inflammation following a HFD. Macrophages from control, but not STING^gt mice, increased markers of inflammation in response to lipopolysaccharide and cGAMP. Hepatocytes and stellate cells co-cultured with STING^gt macrophages in the presence of DMXAA, or incubated with the medium collected from these macrophages, had decreased fat deposition and markers of inflammation compared to hepatocytes incubated with control macrophages. We found levels of STING to be increased in liver tissues from patients with NAFLD mice with HFD-induced steatosis. In mice, loss of STING from liver macrophages reduces the severity of fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD.

Co-infection of avian leukosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV) in poultry flocks induces synergistic replication, which worsens immunosuppression, growth inhibition, and increased mortality. However, the synergistic replication mechanism between ALV-J and REV is still not fully understood. We showed that microRNA-155 (miR-155) targets a dual pathway, PRKCI-MAPK8 and TIMP3-MMP2, which interacts with the U3 region of ALV-J and REV to promote synergistic replication between ALV-J and REV. Initially, we found that the RNA levels of ALV-J and REV increased significantly in ALV-J and REV co-infected cells and tissues compared with mono-infected cells and tissues. Next, miRNAomics showed that ALV-J and REV synergistically increased miR-155 levels. In co-infected cells, miR-155 promoted synergistic replication of ALV-J and REV. All structural proteins of the two viruses activated the expression of miR-155, especially gag proteins, rather than insertional activation. Proteomic study of cells co-infected with ALV-J and REV and transfected with miR-155 indicated that miR-155 directly suppressed PRKCI and TIMP3 and that PRKCI directly prevented MAPK8 expression, while TIMP3 directly interfered MMP2 expression. We also found that MAPK8 and MMP2 co-interacted with ALV-J and REV’s U3 to enhance synergistic replication. In conclusion, ALV-J and REV synergistically activate miR-155, facilitating the synergistic replication of ALV-J and REV by PRKCI-MAPK8 and TIMP3-MMP2 dual-pathway interaction with the U3 region of ALV-J and REV. This discovery will assist in explaining how two retroviruses replicate synergistically. IMPORTANCE: The synergy of two oncogenic retroviruses is an essential phenomenon in nature. The synergistic replication of ALV-J and REV in poultry flocks increases immunosuppression and pathogenicity, extends the tumor spectrum, and accelerates viral evolution, causing substantial economic losses to the poultry industry. However, the mechanism of synergistic replication between ALV-J and REV is still incompletely elusive. We observed that microRNA-155 targets a dual pathway, PRKCI-MAPK8 and TIMP3-MMP2, interacting with the U3 region of ALV-J and REV, enabling synergistic replication. This work gives us new targets to modulate ALV-J and REV’s synergistic replication, guiding future research on the mechanism.

Background/Objectives : Autoimmune metaplastic atrophic gastritis (AMAG) is a chronic, autoimmune-mediated condition associated with increased risk of malignancy and nutritional deficiencies, yet diagnostic and follow-up processes remain inconsistent and unclear. This study investigates follow-up testing performance in patients with AMAG and neuroendocrine tumors (NET), as well as the correlation between endoscopic impressions and histologic findings. Methods: We retrospectively analyzed 65 gastric biopsies with final diagnoses or comments mentioning the possibility of AMAG, 12 of which included well-differentiated WHO grade 1 NET arising in AMAG. H&E slides were reviewed to assess atrophy severity, the presence or absence of enterochromaffin-like (ECL) cell hyperplasia, and Helicobacter organisms. The final diagnostic line or comments made were scored from 1 to 5, based on the strength of the language used to alert the treating clinician to the likelihood of AMAG. Corresponding endoscopy reports were scored from 1 to 5 based on the likelihood of the reports documenting AMAG features. Data regarding follow-up laboratory testing relevant to AMAG and biopsy performance were collected from the electronic medical records. Results: Endoscopy scores showed no significant associations with the histology comment score or atrophy grade. The histology comment score was positively associated with performing at least a total of three laboratory tests (p = 0.03). No association was found between the presence or absence of follow-up biopsy and histology comment score (p = 0.60). Follow-up biopsy was more common in patients with NET than those with AMAG without NET (p < 0.001). Conclusions: Poor endoscopic–histologic correlation with variable follow-up practices highlights the need for standardized protocols in AMAG management. Enhanced adherence to biopsy guidelines, standardized pathology reporting, and consistent surveillance, particularly for patients with AMAG without NET, are imperative to improve diagnosis and outcomes. Future research should focus on optimizing endoscopic techniques, standardizing serological tests, and establishing evidence-based surveillance protocols for AMAG patients.