Haibo Su

Trained immunity induced by β‐glucan insult drives the functional reprogramming of macrophages to the hyperinflammatory status, contributing to developing or maintaining inflammatory diseases. Inflammatory arthritis is characterized by an idiopathically hyperinflammatory response, a phenotype similar to that of trained immunity, and its etiology involves environmental factors such as β‐glucan exposure. However, whether trained immunity contributes to inflammatory arthritis progression, as well as the reciprocal interactions, remains elusive. The study shows that β‐glucan‐induced experimental trained immunity heighten inflammation and arthritis severity in collagen‐induced arthritis (CIA) rat model. Trained macrophages by β‐glucan, upon adoptive transfer, further intensify symptoms. In arthritis progression, trained macrophages reduce fibroblast‐like synoviocytes’ (FLS) lipid peroxidation, lessening sensitivity to iFSP1‐induced ferroptosis through interleukin‐1 beta (IL‐1β)/N‐acetyltransferase 10 (NAT10)/ferroptosis suppressor protein 1 (FSP1) mRNA ac4C modification. A therapeutic approach targeting trained immunity, combining low‐dose iFSP1 and Remodelin, mitigates arthritis severity and restores ferroptosis sensitivity. Additionally, this interplay between CIA induction and β‐glucan training creates a feedback loop reinforcing trained immune memory, accelerating disease deterioration. The findings highlight trained immunity induced by endogenous or exogenous insult, such as β‐glucan, as an unexplored mechanism of inflammation dysregulation in the pathogenesis of inflammatory arthritis, opening avenues for the therapeutic approaches by targeting trained immunity.

To successfully metastasize, cancer cells must evade detachment induced cell death, known as anoikis. Unraveling the mechanisms that gastric cancer (GC) circumvent anoikis and achieve peritoneal metastasis especially during unanchored growth, could significantly improve patient outcomes. Our study reveals that GC cells exhibit increased lipid peroxidation, MDA production, and cell death during suspension culture, which can be mitigated by the intervention with liproxstatin-1 and ferrostatin-1. We discovered that oleic acid (OA) or adipocytes stimulate lipid accumulation in GC cells, thereby inhibiting lipid peroxidation and cell death. Lipid mass spectrometry confirmed an upregulation of triglyceride synthesis, indicating that the accumulation of lipid droplet may confer resistance to ferroptosis during suspension growth. In vitro assays demonstrated that OA not only induces lipid droplet accumulation but also upregulates the expression of ferroptosis suppressor protein 1 (FSP1), a process that can be abrogated by the double knockout of GPD1/1L genes. Additionally, we have demonstrated that a decrease in the ubiquitination of FSP1 in GC cells upon lipid droplet accumulation, as well as silencing or pharmacological targeting FSP1, promotes ferroptosis and disrupts the peritoneal metastatic potential of GC cells. Collectively, our findings highlight the potential of FSP1 as a promising therapeutic target for metastatic gastric cancer.

TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (Mtb) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized Mtb lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M. smegmatis_Rv1016c under stress conditions. We found that Rv1016c lipoprotein was a novel TLR2 ligand and able to induce macrophage apoptosis in a both dose- and time-dependent manner. Additionally, apoptosis induced by Rv1016c was reserved in THP-1 cells blocked with anti-TLR-2 Abs or in TLR2-/- mouse macrophages, indicating that Rv1016c-induced apoptosis is dependent on TLR2. Moreover, we demonstrated that Rv1016c lipoprotein inhibited IFN-γ-induced MHC-II expression and processing of soluble antigens in a TLR2 dependent manner. Class II transactivator (CIITA) regulates MHC II expression. In this context, Rv1016c lipoprotein diminished IFN-γ-induced expression of CIITA IV through TLR2 and MAPK Signaling. TLR2-dependent apoptosis and inhibition of MHC-II Ag processing induced by Rv1016c during mycobacteria infection may promote the release of residual bacilli from apoptotic cells and decrease recognition by CD4+ T cells. These mechanisms may allow intracellular Mtb to evade immune surveillance and maintain chronic infection.