Interleukin-1α released from HSV-1-infected keratinocytes acts as a functional alarmin in the skin

Herpes simplex virus-1 (HSV-1) is a human pathogen that utilizes several strategies to circumvent the host immune response. An immune evasion mechanism employed by HSV-1 is retention of interleukin-1 beta (IL-1 beta) in the intracellular space, which blocks the pro-inflammatory activity of IL-1 beta. Here we report that HSV-1-infected keratinocytes actively release the also pro-inflammatory IL-1 alpha, preserving the ability of infected cells to signal danger to the surrounding tissue. The extracellular release of IL-1 alpha is independent of inflammatory caspases. In vivo recruitment of leukocytes to early HSV-1 microinfection sites within the epidermis is dependent upon IL-1 signalling. Following cutaneous HSV-1 infection, mice unable to signal via extracellular IL-1 alpha exhibit an increased mortality rate associated with viral dissemination. We conclude that IL-1 alpha acts as an alarmin essential for leukocyte recruitment and protective immunity against HSV-1. This function may have evolved to counteract an immune evasion mechanism deployed by HSV-1.