HSP90, a common therapeutic target for suppressing skin injury caused by exposure to chemically diverse classes of blistering agents

Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence, developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES) respectively, we defined a common underlying mechanism of toxic action by these two distinct classes of vesicants. Murine skin exposure to these chemicals causes tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells and appearance of apoptotic epidermal and dermal cells. RNAseq analysis identified ~346 inflammatory genes that were commonly altered by both PAO and CEES along with identification of cytokine signaling activation as the top canonical pathway. Activation of several of these inflammatory genes and pathways are associated with phosphorylation-dependent activation of heat shock protein 90α (p-HSP90α). Topical treatment with known HSP90 inhibitors, SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuated these chemical-induced skin damage (reduction in overall skin injury and clinical scores). In addition, highly upregulated inflammatory genes Saa3, Cxcl1, Ccl7, IL-6, Nlrp3, Csf3, Chil3 etc. by both PAO and CEES, were significantly diminished by the treatment with these HSP90 inhibitors. These drugs not only reduced PAO or CEES-induced p-HSP90α expression but also its client proteins NLRP3, pP38 and expression of their target inflammatory genes. Our data confirm a critical role of HSP90 as a shared underlying molecular signaling of toxicity by these two distinct vesicants and provide an effective and novel medical countermeasure to suppress vesicants -induced skin injury. Significance Statement Development of effective and novel mechanism-based antidotes which can simultaneously block cutaneous toxic manifestations of distinct vesicants is important and urgently needed. Due to difficulties in determining the exact nature of onsite chemical exposure, a potent drug that can suppress widespread cutaneous damage may find a great utility. Thus, we identified HSP90 as a common molecular regulator of cutaneous inflammation and injury by two distinct warfare vesicants: arsenicals and mustards; and HSP90 inhibitors afford significant protection against skin damage.