Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome

Abstract

Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by genetically regulating Tim-3 and its ligand Gal-9. Tim-3/Gal-9 regulation was positively correlated with the NLRC4 inflammasome, NLRC4, and caspase-1 expression. Tim-3/Gal-9 did not trigger IL-1β secretion but were strongly positively correlated with caspase-1 activity as they induced programmed cell death in glioma cells. A protein–protein interaction analysis revealed that the FYN-JAK1-ZNF384 pathways are bridges in NLRC4 inflammasome regulation by Tim-3/Gal-9. The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome.

Comparing the Expression of Canonical and Non-Canonical Inflammasomes Across Glioma Grades: Evaluating Their Potential as an Aggressiveness Marker

“…Additionally, our previous study revealed that the binding of T cell immunoglobulin and the mucin-domain containing-3 (Tim-3), a representative immune checkpoint molecule in glioma, and its ligand, gal-9, induces the NLRC4 inflammasome [ 53 ]. Tim-3/gal-9 showed a positive correlation with NLRC4 and caspase-1, and their expression increased with glioma grade and was associated with poor survival in patients with glioma [ 53 ]. The inflammasome is also associated with T cell-related immune responses and can affect the inflammatory tumor microenvironment in various ways, and its control can be used for the treatment of glioma.…”

TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors

“…As the inflammatory microenvironment and immune escape are hallmarks of glioma progression, in many tumors, these mechanisms are interrelated and cooperate in the malignant transformation of cancer [ 55 – 57 ]. During glioma progression, tumor cells modulate the expression profile of immune checkpoint molecules and their ligands [ 58 ]. TIM-3 receptor modulates microglia function and regulates the interaction of microglia with nerve cells [ 59 ].…”

“…The binding between Tim-3 and Gal-9 promotes tumor growth and suppresses the adaptive immune system [ 62 ]. A study by Simet al found that the Tim-3/Gal-9 axis association with the NLRC4 inflammasome contributes to glioma development [ 58 ]. Tim-3/Gal-9 regulation was positively correlated with NLRC4 inflammasome, NLRC4, and caspase-1 expression.…”