The aim of this study was to explore the precise role of retinoic acid-inducible gene-I (RIG-I) signaling in human immunodeficiency virus type 1 (HIV-1)-infected macrophages from patients with HIV-1-associated neurocognitive disorders (HAND). Postmortem brain tissues were collected from patients with HIV-1-associated dementia and were compared to samples collected from HIV serum-positive patients without dementia and HIV serum-negative patients. A human monocyte-derived macrophage (MDM) primary culture system was established to evaluate the expression of RIG-I in these samples. Knockdown of RIG-I pathways genes was employed and STAT1 expression and phosphorylation levels were examined to explore the molecular mechanisms of HAND. The expression of RIG-I in postmortem brain tissue from HAND patients was significantly higher than in patients who were HIV serum-positive without dementia or HIV serum-negative. Moreover, we demonstrated that HIV-1 infection could result in a significant increase in the level of RIG-I in human MDMs. Moreover, a correlation was found between the increase in RIG-I expression and STAT1 expression and phosphorylation. Accordingly, knockdown of RIG-I decreased the phosphorylation of STAT1 and downregulated interferon-related genes. These observations highlight the importance of RIG-I signaling in anti-HIV innate immunity in macrophages, which may be beneficial for the treatment of HIV and aid in the understanding of the neuropathogenesis of HAND.

KRAS mutations are causally linked to pro-tumor inflammation and identified as driving factors in tumorigenesis. Here, using multi-omics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS mutant iCCA. In KRAS mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant anti-tumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in KRAS mutant iCCA patients were significantly associated with superior response to anti-PD-1 immunotherapy.