¹ Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA.

² Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.

³ Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA.

⁴ Pittsburgh Center for Pain Research, Pittsburgh, PA, USA.

⁵ Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which scratching exacerbates inflammation and whether scratching provides benefit to the host are largely unknown. We found that scratching was required for skin inflammation in mouse models dependent on FcεRI-mediated mast cell activation. Scratching-induced inflammation required pain-sensing nociceptors, the neuropeptide substance P, and the mast cell receptor MrgprB2. Scratching also increased cutaneous inflammation and augmented host defense to superficial Staphylococcus aureus infection. Thus, through the activation of nociceptor-driven neuroinflammation, scratching both exacerbated allergic skin disease and provided protection from S. aureus , reconciling the seemingly paradoxical role of scratching as a pathological process and evolutionary adaptation.