How Neutrophils' Defenses Might Backfire

Neutrophils are the body's first line of defense. They release something called neutrophil extracellular traps, or NETs, during inflammation. These NETs are like a web that catches and kills invaders. But this web has a twist. It's made of DNA, histones, and other proteins, including an enzyme called myeloperoxidase (MPO). MPO produces a substance called hypochlorous acid, which is great at killing germs. However, this acid can also change the proteins in NETs, including histones. This change is called a post-translational modification, and it can alter how these proteins behave. Researchers wanted to see if these changes happen and if they matter. They collected NETs from neutrophils and a cell line called PLB-985. They stimulated these cells with two different substances: phorbol myristate acetate (PMA) and nigericin, a bacterial peptide. They found that the histones and other proteins in NETs had indeed been changed by the hypochlorous acid. These changes included things like Lys nitrile formation, Tyr and Trp chlorination, and Met oxidation. One change, in particular, stood out: the chlorination of Tyr-88 on histone H4. This change was more common in NETs from cells exposed to PMA than nigericin. This is because nigericin triggers NET release in a way that doesn't involve oxidation. These findings are important because they show that the body's defense mechanism might have unintended consequences. The changes to histones and other proteins in NETs could potentially contribute to disease. For instance, the chlorination of histone H4 Tyr-88 was also found in the nuclear and cytoplasmic extracts of stimulated cells. This change could be reduced by treating the neutrophils with an MPO inhibitor called AZD5904. This suggests that controlling MPO activity could potentially prevent these unwanted changes. But why does this matter? Well, understanding how NETs work and how they might contribute to disease could lead to new treatments. For example, if we can find a way to control the changes that hypochlorous acid makes to proteins in NETs, we might be able to prevent or treat certain diseases. This is still a topic of ongoing research, but it's an exciting area with a lot of potential. In the end, the body's defense mechanisms are complex. They're designed to protect us, but they can also cause harm if not properly regulated. Understanding these processes is key to developing better treatments and improving health outcomes. It's a reminder that even our body's defenses need a bit of fine-tuning sometimes.