Regulation of Sterile Inflammatory Responses By Mitochondria-Associated Proteins

Inflammation is an important defense mechanism through which cells respond to pathogenic insults and damage/stress signals. Immune cells mediate extracellular inflammatory responses by synthesizing and releasing small proteins called cytokines, which play critical roles in modulating these responses. Specifically, key pro-inflammatory cytokines such as IL-1beta are released upon the assembly and activation of a multi-protein intracellular complex called the inflammasome, the most well-studied of which is the NLRP3 inflammasome. Several proteins have been identified as important regulators of cellular stress responses, including vacuole membrane protein 1 (VMP1). The present research shows that VMP1-depleted cells exhibit exacerbated cellular inflammation and are prone to mitochondrial damage using a CRISPR/Cas9 VMP1-knockout THP-1 model. Similarly, a component of the complement system, the C5a receptor, has been shown to mediate cellular stress responses by interacting on the mitochondrial surface. Present research explores the effects of a CRISPR/Cas9 C5a-knockout system on cellular inflammation in THP-1 cells.