Corticosteroids are regularly used for treatment of autoimmune diseases, such as bullous pemphigoid (BP). In BP, autoantibodies bind to type XVII collagen (COL17), located at the dermal-epidermal junction (DEJ). A crucial role of neutrophils in experimental BP has been established. Specifically, reactive oxygen species (ROS) and proteolytic granule enzymes mediate tissue injury. Therefore, we investigated effects of methylprednisolone (MP) on neutrophils, which are likely to be affected by topical treatment. First, MP inhibited dermal-epidermal separation ex vivo in cryosections of human skin induced by co-incubation of BP autoantibodies with neutrophils from healthy volunteers. Next, MP inhibited neutrophil activation in vitro induced by immune complexes (IC) of COL17 and autoantibodies. This neutrophil activation was associated with phosphorylation of ERK1/2, p38 MAPK and Akt. In turn, inhibition of ERK1/2, p38 MAPK or Akt phosphorylation inhibited neutrophil activation by IC in vitro and dermal-epidermal separation ex vivo. Additionally, we observed an increase of p38 phosphorylation in dermal infiltrates of BP patients. Treatment of mice with either MP or inhibitors of p38- or ERK1/2 phosphorylation impaired induction of autoantibody- or irritant-induced neutrophil-dependent inflammation. We here identify inhibition of Akt, ERK1/2 and p38 MAPK phosphorylation as molecular mechanisms to promote MP's therapeutic effects.Journal of Investigative Dermatology accepted article preview online, 28 February 2013; doi:10.1038/jid.2013.91.