CITH3 is a significant biological molecule, a modified protein involved in various bodily processes, especially those related to the immune system and inflammation. Understanding CITH3’s role offers insights into how our bodies respond to challenges and maintain balance. Its involvement in fundamental biological activities underscores its broader relevance in health and disease.
What is CITH3?
CITH3 stands for Citrullinated Histone H3, a modified form of histone H3. Histones are proteins that act as spools around which DNA is wound, packaging DNA into chromosomes within the cell nucleus. The modification in CITH3 involves citrullination, where the amino acid arginine within the histone protein is converted into citrulline. This chemical change is catalyzed by enzymes known as peptidylarginine deiminases (PADs), specifically PAD2 and PAD4.
CITH3 is not found free in the blood under normal conditions. It is primarily associated with neutrophil extracellular traps (NETs). These NETs are web-like structures composed of DNA, histones, and antimicrobial proteins released by neutrophils, a type of white blood cell, as a defense mechanism against pathogens. When NETs are formed and released, CITH3 becomes detectable outside the cells.
How CITH3 Functions in Cells
CITH3’s function is closely tied to its role in neutrophil extracellular trap (NET) formation, an immune defense mechanism. During NETosis, a form of cell death, neutrophils release their nuclear contents, including DNA and histones, into the extracellular space. This expulsion forms a sticky, mesh-like structure that traps and neutralizes invading microbes. The citrullination of histone H3 by PAD enzymes is an early step in this process.
This modification leads to the decondensation of chromatin, allowing the DNA to unfurl and form the backbone of NETs. Beyond its structural contribution to NETs, CITH3 also acts as a damage-associated molecular pattern (DAMP). When released, CITH3 can activate immune receptors and amplify inflammatory signaling pathways. This can perpetuate a cycle of inflammation, contributing to tissue damage.
CITH3 and Human Health
The presence of CITH3 in the bloodstream has implications for human health. Elevated levels are observed in various inflammatory conditions, indicating its involvement in disease. For instance, CITH3 is a potential biomarker for sepsis, a severe response to infection. In mouse models of endotoxic shock, CITH3 levels rise quickly, within 30 minutes, and remain elevated for up to 24 hours.
CITH3’s sustained presence in the blood during sepsis distinguishes it from other biomarkers. Beyond sepsis, increased CITH3 levels have been linked to viral infections, ischemia-reperfusion injury, and autoimmune diseases. It contributes to inflammation by disrupting endothelial barriers, which can increase vascular permeability and worsen inflammatory responses. The release of CITH3 from NETs can damage multiple cell types, including endothelial, epithelial, immune, and neural cells, leading to multi-organ dysfunction.
CITH3 Research and Therapeutic Potential
Research focuses on CITH3 as a promising target for diagnostic and therapeutic strategies. Scientists are developing specific assays, such as enzyme-linked immunosorbent assays (ELISA), to accurately measure circulating CITH3 levels in blood samples, providing reliable data for research and clinical applications. The development of novel antibodies that specifically target CITH3 aims to improve detection and neutralization.
Studies in animal models show that neutralizing circulating CITH3 with specific antibodies can reduce inflammatory responses, mitigate organ damage, and improve survival rates in conditions like endotoxic shock. This suggests CITH3 could be a druggable target, offering a pathway for new treatments for acute and chronic inflammatory diseases. Ongoing investigations aim to translate these findings into clinical applications, potentially leading to improved diagnostic tools and therapeutic interventions.