Why do we scratch? Scratching in response to itching is both pleasurable and harmful. In skin conditions, particularly dermatitis, scratching creates a vicious cycle, intensifying the itch and worsening symptoms. However, scratching remains an irresistible behavior in humans and animals, including fish, suggesting an evolutionary purpose preserved over millions of years.
A recent study on mice published in the journal Science revealed that scratching regulates the immune response and composition of the skin microbiome, potentially evolving as a defense against skin infections.
To understand the role of scratching in the inflammatory response, researchers used genetically modified mice without neurons responsible for itch, identified by MrgprA3 gene expression. These MrgprA3 neurons, activated by immunoglobulin E, trigger an itching sensation. Mice without MrgprA3 showed no itch sensation and failed to develop an inflammatory response, including neutrophil infiltration and mast cell activation, when exposed to allergens. The same occurred in normal mice that wore collars to prevent them from scratching. This indicates that scratching, not itching, is necessary to induce a local immune response.
Further experiments revealed that scratching triggers a neuroimmune pathway that starts from TRPV1-expressing neurons that release substance P, a neuropeptide released by pain-sensing neurons during scratching. Substance P, in turn, acts on mast cells, inducing the release of tumor necrosis factor, resulting in increased inflammation.
Inhibition of TRPV1-expressing neurons or substance P secretion blocked the scratching-induced immune response. Conversely, activating TRPV1-expressing neurons with capsaicin triggered the same immune response observed after scratching.
Why does this immune cascade involve itching and scratching? Couldn't itch-inducing neurons directly activate mast cells? Further experiments reveal that scratching plays a crucial role in regulating the skin microbiome.
In fact, studies in mice show that scratching alters the microbiome composition at the affected site. Several bacterial genera, particularly potentially pathogenic bacteria such as Staphylococcus aureus, decline in response to scratching.
These findings suggest that scratching serves as a dual defense mechanism: On the one hand, it reduces pathogenic bacteria, lowering the risk for infection, and on the other, it activates mast cells, enabling the skin to mount a strong immune response against bacterial infections.
This study reconciles the paradoxical role of scratching as a pathologic process and evolutionary adaptation with its harmful effects in conditions such as dermatitis. While scratching is a behavior with benefits, at least in the contexts for which it evolved, it can also worsen several skin diseases by directly causing inflammation.
Understanding the molecular and immune mechanisms underlying itching has revealed a neuroimmune pathway with therapeutic benefits. Future treatments could alleviate itching more effectively, such as in chronic conditions, by reducing the negative aspects of scratching, such as excessive inflammation, while maintaining the positive aspects of antimicrobial defense.