Excessive, constant inflammation in response to aspects of one's own cellular biochemistry is a feature of both autoimmune disease and aging. While transient inflammation is necessary for effective regeneration and defense against pathogens, constant unresolved inflammatory signaling is destructive to tissue structure and function. It is a major component of the pathology of common age-related conditions. The challenge in addressing this is that unwanted inflammation and desirable inflammation both involve the same molecular signals and points of control. To date, therapies that reduce chronic inflammation do so via crude blockade of signals or mechanisms, with the side effect of reduced immune capability, a reduction in the normal immune response when it is needed. The research community is slowly making progress towards finding points of distinction, however, approaches to intervention that have greater effects on unwanted inflammation than they do on the normal immune response. One such line of work is noted here, focused on autoimmunity.
Current autoimmune disease treatments like hydroxychloroquine work by broadly blocking endosomes, the compartments inside cells where incoming materials are sorted and processed, including molecules that trigger immune responses. While effective, this approach can lead to significant side effects - including gastrointestinal problems and, less commonly, vision damage-causing a significant number of patients to stop treatment.
Researchers focused on two proteins, Munc13-4 and syntaxin 7, that must bind together for immune sensors called Toll-like receptors (TLRs) to activate inside endosomes. This "molecular handshake" plays a key role in detecting the foreign DNA and RNA from invaders like viruses and bacteria. However, in autoimmune diseases, TLRs become overactive, detecting self-nucleic acids, for example, from neutrophil-extracellular traps, and trigger chronic, damaging inflammation even without a real threat.
The team screened roughly 32,000 compounds and identified molecules that specifically block the Munc13-4-syntaxin 7 interaction without disrupting other cellular functions. Because Munc13-4 is found mainly in immune cells, the compounds offer a targeted way to calm inflammation. "Most treatments for autoimmune diseases manage symptoms; they don't change the underlying course of the disease. What's exciting about this approach is its potential to be disease-modifying: targeting the specific molecular machinery that drives inflammation, rather than broadly suppressing the immune system."
The most potent compound, ENDO12, reduced inflammation in animal models that were also given a TLR-activating molecule. Blood levels of inflammatory markers - including immune system activators IL-6 and IFN-γ, and the enzyme myeloperoxidase - dropped significantly in those that were treated. Crucially, ENDO12 did not impair the animal models' ability to fight a real viral infection: they showed a normal antiviral immune response when exposed to a virus. This selectivity addresses a major concern with immunosuppressive drugs: that dampening inflammation might leave patients vulnerable to infections.
Link: https://www.scripps.edu/news-and-events/press-room/2026/20260406-catz-endotollins.html
View the full article at FightAging
