UC San Diego

The skin serves a vital role as our body’s first line of defense against the external environment and the potentially pathogenic microbes we encounter. However, abundant, diverse communities of microbial species colonize the skin shortly after birth and evolve with us over time. Thus, the skin exists in a unique immunological state, where it must tolerate and avoid reacting to these resident microbes under normal conditions while remaining poised to respond rapidly and effectively at the first sign of danger. To accomplish this feat, tight regulation of the inflammatory and immune processes present in the skin is crucial.

This dissertation begins with a description of the processes relevant to the maintenance of immunological homeostasis in the skin. In particular, the complex network of immune functions present in the skin is discussed, with a focus on the innate immune processes active in the epidermis and the role of keratinocytes in host defense. Additionally, we introduce the concept of epigenetic regulation of gene expression and discuss the roles of histone modifications, chromatin structure, and regulatory nuclear factors. The skin microbiome is described in detail, as are the impacts of these skin-resident microbes on cutaneous immunological processes and the consequences that can arise when their composition is altered.

Next, the hypothesis that the microbiome can influence epigenetic regulation of inflammatory gene expression in keratinocytes is explored. This work describes how a particular member of the skin microbiome can generate molecules that inhibit histone deacetylase (HDAC) activity, which has distinct effects in different cell types of the cutaneous innate immune system—specifically, an enhancement of TLR-mediated proinflammatory gene expression in keratinocytes. Furthermore, HDAC8 and HDAC9 are identified as key regulators of inflammatory gene expression in keratinocytes, as depletion of either of these enzymes greatly enhances the response to TLR activation.

Taken together, these results enhance our understanding of the impact of resident microbes on the immunological functions of the skin, and identify a mechanism by which tolerance to these microbes can be broken. This work advances our knowledge of the host-microbe interactions occurring at epithelial surfaces, and introduces a novel way of thinking about the mechanisms underlying the initiation and pathogenesis of inflammatory skin conditions.