Irritant contact dermatitis (ICD) is one of the most common inflammatory skin diseases caused by exposure to chemical irritants. Since chemical irritants primarily damage keratinocytes, these cells play a pivotal role in ICD. One of the phosphoinositide-metabolizing enzymes, phospholipase C (PLC) delta 1, is abundantly expressed in keratinocytes. However, the role of PLC delta 1 in ICD remains to be clarified. Here, we found that croton oil (CrO)-induced ear swelling, a feature of ICD, was attenuated in keratinocyte-specific PLC delta 1 knockout mice (PLC delta 1 cKO mice). Dendritic epidermal T cells (DETCs), which have a protective role against ICD, were activated in the epidermis of the PLC delta 1 cKO mice. In addition, the skin of CrO-treated PLC delta 1 cKO mice showed increased infiltration of Gr1(+)CD11b(+) myeloid cells. Of note, elimination of Gr1(+)CD11b(+) myeloid cells restored CrO-induced ear swelling in PLC delta 1 cKO mice to a similar level as that in control mice. Taken together, our results strongly suggest that epidermal loss of PLC delta 1 protects mice from ICD through induction of Gr1(+)CD11b(+) myeloid cells and activation of DETCs. (C) 2019 Elsevier Inc. All rights reserved.