A new study investigating how the innate immune system is controlled identified a protein that acts as a negative regulator of the toll-like receptor (TLR) signaling pathway, which controls immune response. The study findings help advance the understanding of auto-immune disorders, atherosclerosis, and heart disease, potentially leading to improved prevention and treatments. The paper describing the study was published in the Journal of Clinical Investigation.
The research team found that somatic nuclear autoantigenic sperm protein (sNASP), an inhibitory protein, binds to TRAF6, a signaling molecule that starts the toll-like receptor (TLR) signaling pathway which activates the innate immune response. The study showed that in unstimulated cells, sNASP binds to TRAF6, preventing an accidental immune response. Activation of the innate immune system through TLR signaling needs to be tightly regulated—hypoactivation or hyperactivation can cause disease in humans. When an immune response was stimulated with LPS, the team observed that sNASP became phosphorylated and released from TRAF6 which allowed TRAF6 to begin the downstream TLR signaling cascade. In mice engineered to overexpress sNASP, the inhibitory protein remained bound to TRAF6 which prevented the mice from developing an immune response making them more susceptible to sepsis. A closer look showed that these mice had a marked reduction in cytokines and the inability to recruit leukocytes to fight the infection.
"The innate immune response is a critical component of immunity. Our finding identifies a novel way that immune response can be controlled, which can be translated to many human diseases, such as atherosclerosis, autoimmunity and heart failure," said Dr. Edward T.H. Yeh, chairman of the Department of Medicine and director of the Center for Precision Medicine at the University of Missouri School of Medicine.
Overall, the study reveals a previously unrecognized role for sNASP as a negative regulator of TLR signaling, the pathway that controls the innate immune response. The research team is currently investigating how mutations in sNASP would impact the development of atherosclerosis and heart failure.