Keratinocytes regulating Skin Inflammation Pemphigoid Diseases

The contribution of keratinocytes to the orchestration of PD skin inflammation is still elusive. Using keratinocyte-specific RelA-deficient (RelAepi) mice, we have recently found that activation of the key transcription factor NF-κB, specifically in keratinocytes, is indispensable for the eruption of full-blown skin inflammation in the AAb transfer EBA model. Thus, keratinocyte-specific deficiency in RelA (p65), an essential component of the major heterodimer constituting NF-κB, suppressed effector cell recruitment and clinical signs of skin inflammation down to a mild degree, suggesting that keratinocytes play a previously unappreciated role in the orchestration of PD skin inflammation and broadly amplify effector cell recruitment into the skin. Kinetics and mechanism(s) of NF-κB activation as well as the mechanisms that NF-κB consequently applies to aggravate inflammation, however, are still elusive. Likewise, it is unclear, whether NF-κB activation in keratinocytes in PD is a local phenomenon, restricted to emerging skin lesions, or if it generalized throughout the complete integument. While keratinocytes are presumably activated by crosstalk with infiltrating effector cells, there is also evidence that PD autoantibodies, specifically anti-type VII and anti-type XVII collagen AAbs, can directly activate keratinocytes and elicit the release of PD-relevant mediators, including CXCR2 ligands and IL-1β, by unknown mechanisms. We therefore hypothesize that in emerging skin inflammation, NF-κB is activated in keratinocytes, partially by mediators derived from the dermal infiltrate and partially by direct interaction with PD-specific AAbs. Thereupon, keratinocytes release proinflammatory mediators, which broadly amplify effector cell recruitment into the skin.
To test these hypotheses, we will pursue the following Specific Aims: (i) To determine kinetics and mechanisms of NF-κB activation in keratinocytes in PD, (ii) To unravel the molecular mechanisms that NF-κB activation in keratinocytes initiates to drive PD skin inflammation, and (iii) To evaluate the therapeutic potential of epidermal NF-κB inhibition in PD treatment. This project will elucidate the role of epidermal NF-κB activation in PD. The results will further illuminate the previously unappreciated regulatory role of keratinocytes in PD skin inflammation and will this way significantly add to model the processes driving PD skin inflammation. NF-κB is a most important master switch for inflammation. Great effort has been put into developing drugs inhibiting NF-κB. Its systemic inhibition, however, is linked to severe toxicities. In PD, NF-κB inhibition in keratinocytes appears sufficient to ameliorate disease; rendering NF-κB possibly amenable for topical drug application and limiting toxicity.