LRRC25 Inhibits IFN-γ Secretion by Microglia to Negatively Regulate Anti-Tuberculosis Immunity in Mice

Abstract

Background: Leucine-rich repeat-containing protein-25 (LRRC25) can degrade the ISG15 gene in virus-infected cells and prevent overactivation of the type Ⅰ IFN pathway. However, the role of LRRC25 in bacterial infection is still unclear. In this pursuit, the present study aimed to explore the regulatory role and mechanism of LRRC25 in microglia infected with Mycobacterium tuberculosis in a mouse model. Methods: Q-PCR, WB, and cell immunofluorescence were employed to observe the change in LRRC25 in BV2 cells infected by H37Rv. Additionally, siRNA was designed to target the LRRC25 to inhibit its expression in BV2 cells. Flow cytometry and laser confocal imaging were used to observe the infection of BV2 cells after LRRC25 silencing. Q-PCR and ELISA were used to determine the changes in IFN-γ and ISG15 in the culture supernatant of each group. Results: Following H37Rv infection, it was observed that the expression of LRRC25 was upregulated. Upon silencing LRRC25, the proportion of BV2 cells infected by H37Rv decreased significantly. ELISA analysis showed that IFN-γ and ISG15 levels in cell culture supernatant decreased after H37Rv infection, while they significantly increased after LRRC25 silencing. Conclusions: This study provides evidence that LRRC25 is the key negative regulator of microglial anti-Mtb immunity. It exerts its function by degrading free ISG15 and inhibiting the secretion of IFN-γ, thereby improving the anti-Mtb immunity of BV2 cells.

LRRC25 expression during physiological aging and in mouse models of Alzheimer’s disease and iPSC-derived neurons

“…In recent years neuroinflammation has emerged as a third hallmark feature of AD ( Leng and Edison, 2021 ; Zhou et al, 2021 ; Mangalmurti and Lukens, 2022 ). LRRC25’s role in neuroinflammation in AD is also intriguing given that LRRC25 overexpression impairs and LRRC25 knockout potentiates NF-κB activation thereby increasing the production of inflammatory cytokines ( Feng et al, 2017 ), More recently LRRC25 has also been shown to inhibit IFN-γ secretion by microglia ( Sheng et al, 2023 ). It is important to note that the anti-inflammatory role of LRRC25 has been demonstrated in response to viral infections.…”