Differential Expression Profile of NLRs and AIM2 in Glioma and Implications for NLRP12 in Glioblastoma

Abstract

Gliomas are the most prevalent primary brain tumors with immense clinical heterogeneity, poor prognosis and survival. The nucleotide-binding domain, and leucine-rich repeat containing receptors (NLRs) and absent-in-melanoma 2 (AIM2) are innate immune receptors crucial for initiation and progression of several cancers. There is a dearth of reports linking NLRs and AIM2 to glioma pathology. NLRs are expressed by cells of innate immunity, including monocytes, macrophages, dendritic cells, endothelial cells, and neutrophils, as well as cells of the adaptive immune system. NLRs are critical regulators of major inflammation, cell death, immune and cancer-associated pathways. We used a data-driven approach to identify NLRs, AIM2 and NLR-associated gene expression and methylation patterns in low grade glioma and glioblastoma, using The Cancer Genome Atlas (TCGA) patient datasets. Since TCGA data is obtained from tumor tissue, comprising of multiple cell populations including glioma cells, endothelial cells and tumor-associated microglia/macrophages we have used multiple cell lines and human brain tissues to identify cell-specific effects. TCGA data mining showed significant differential NLR regulation and strong correlation with survival in different grades of glioma. We report differential expression and methylation of NLRs in glioma, followed by NLRP12 identification as a candidate prognostic marker for glioma progression. We found that Nlrp12 deficient microglia show increased colony formation while Nlrp12 deficient glioma cells show decreased cellular proliferation. Immunohistochemistry of human glioma tissue shows increased NLRP12 expression. Interestingly, microglia show reduced migration towards Nlrp12 deficient glioma cells.

Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

“…Reduced mRNA levels of NLRC4 are evident in the tumor tissues of colorectal cancer 118 . However, more recent studies have demonstrated normal levels in lung tumors 119 and hepatocellular carcinoma, 120 along with increased expression in breast cancer and glioma 121,122 . The role of NLRC4 in tumor regulation and suppression is not always consistent even in the same tumor model (Table 4), as discussed further below.…”

PODNL1 Methylation Serves as a Prognostic Biomarker and Associates with Immune Cell Infiltration and Immune Checkpoint Blockade Response in Lower-Grade Glioma

“…The Kaplan-Meier survival curves for CpGs that are significantly prognostic after adjusting for age, gender, tumor grade, and IDH1 mutation are presented in Figure 2(Ci-Civ) for DFS along with forest plot visualization of hazard ratios with 95% CI in Figure 2D. For cg07425555 (Figure 2Ci), the median DFS of high methylation ("Meth") versus low methylation ("Unmeth") was 72 (52-91) months versus 31 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) months (p < 0.001). For cg26969888, the median DFS of Meth versus Unmeth was 63 (44-83) months versus 30 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) months (p < 0.001).…”

Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma

“…The role of NLRP12 in attenuating these inflammatory disorders was explained by the fact that NLRP12 downregulates NF-κB and ERK activation in T cells [71]. Deficiency of NLRP12 also promotes proliferation of osteocytes, hepatocytes, and microglia [28,76,77]. In the intestine, NLRP12-mediated regulation of inflammatory responses may shape gut microbiota composition [78,79].…”