Causal Biological Network Model for Inflammasome Signaling Applied for Interpreting Transcriptomic Changes in Various Inflammatory States

Abstract

Virtually any stressor that alters the cellular homeostatic state may result in an inflammatory response. As a critical component of innate immunity, inflammasomes play a prominent role in the inflammatory response. The information on inflammasome biology is rapidly growing, thus creating the need for structuring it into a model that can help visualize and enhance the understanding of underlying biological processes. Causal biological network (CBN) models provide predictive power for novel disease mechanisms and treatment outcomes. We assembled the available literature information on inflammasome activation into the CBN model and scored it with publicly available transcriptomic datasets that address viral infection of the lungs, osteo- and rheumatoid arthritis, psoriasis, and aging. The scoring inferred pathway activation leading to NLRP3 inflammasome activation in these diverse conditions, demonstrating that the CBN model provides a platform for interpreting transcriptomic data in the context of inflammasome activation.

Tobacco Alkaloid Assessment in a DSS-Induced Colitis Mouse Model with a Fully Humanized Immune System

“…To obtain mechanistic insight into nicotine’s effects on DSS-induced colitis, we used an enrichment approach that relies on a database of over 800 molecular entities or nodes (e.g., protein activities, complexes, chemicals) with mRNAs known to be regulated by the nodes. The activity of these nodes can be inferred by comparing differential mRNA regulation in experimental data to the mRNAs assigned under each node, taking into consideration the expected directionality of the regulation [ 34 , 35 , 36 ]. Hence, the nodes represent inferred changes in protein activity rather than at the mRNA level.…”

Molecular Foundations of Inflammatory Diseases: Insights into Inflammation and Inflammasomes

“…These enzymes further degrade type II collagen and proteoglycans, which are important components of cartilage. Examples of these enzymes are matrix metalloproteinases and thrombospondin motif metalloproteinases [86,108]. The process causes collagen and proteoglycan particles to be released into the joint space, which in turn promotes the production of additional pro-inflammatory cytokines, such IL-18, which promote inflammation and stimulate the joint.…”

Targeting the NLRP3 inflammasome in psoriasis

“…Furthermore, the skin of mice with induced psoriasis, using imiquimod (IMQ), has also exhibited elevated levels of NLRP3 expression, along with increased levels of IL-1b and IL-18. 25 Unbiased sequencing and grid model scoring have revealed that inflammasome activation is the most pronounced in patients with psoriasis, 26,27 and levels of IL-1b and IL-18 are positively correlated with disease severity. 28 These findings suggest that the activation of the NLRP3 inflammasome is present in both patients and IMQ-induced mouse psoriasis models.…”