Interleukin-36β provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses

Interleukin-36 (IL-36) represents three cytokines, IL-36 alpha, IL-36 beta and IL-36 gamma, which bind to the same receptor, IL-1RL2; however, their physiological function(s) remain poorly understood. Here, the role of IL-36 in immunity against HSV-1 was examined using the flank skin infection mouse model. Expression analyses revealed increased levels of IL-36 alpha and IL-36 beta mRNA in infected skin, while constitutive IL-36 gamma levels remained largely unchanged. In human keratinocytes, IL-36 alpha mRNA was induced by HSV-1, while IL-1 beta and TNF alpha increased all three IL-36 mRNAs. The dominant alternative splice variant of human IL-36 beta mRNA was isoform 2, which is the ortholog of the known mouse IL-36 beta mRNA. Mice deficient in IL-36 beta, but not IL-36 alpha or IL-36 gamma, succumbed more frequently to HSV-1 infection than wild type mice. Furthermore, IL-36 beta(-/-) mice developed larger zosteriform skin lesions along infected neurons. Levels of HSV-1 specific antibodies, CD8(+) cells and IFN gamma-producing CD4(+) cells were statistically equal in wild type and IL-36 beta(-/-) mice, suggesting similar initiation of adaptive immunity in the two strains. This correlated with the time at which HSV-1 genome and mRNA levels in primary skin lesions started to decline in both wild type and IL-36 beta(-/-) mice. Our data indicate that IL-36 beta has previously unrecognized functions protective against HSV-1 infection.