Inflammation and Epidermal Barrier Integrity, Decline, and Restoration: It's Time to Rouse the "guardians at the Gate".

Epidermal barrier (EB) function is too often reduced to the role of a passive, inanimate upper strata of dead corneocytes surrounded by extruded lipids. However, this summary fails to appreciate the lower strata keratinocytes (KCs) which serve as both sensors and effectors of immune signaling and thus contribute a dynamic, responsive nature to EB and maintenance and possible decline. In this context, underpinnings of chronic inflammatory skin diseases, e.g. psoriasis and atopic dermatitis, can be better recognized as a feed forward loop in which barrier dysfunction and runaway inflammatory signaling reinforce one another. Traditional therapies addressing these diseases focus on quelling effects and activities of pro-inflammatory extracellular cytokines and their cognate receptors. This paradigm overlooks the promising alternative of augmenting endogenous negative regulators of inflammatory signaling, e.g. the proteins A20 (TNFAIP3) and TNIP1 (ABIN-1) which we propose act as "guardians" restricting NF-κB-dependent inflammatory pathways. Here, we explore the rationale and possible means for targeting these regulators to protect or restore EB integrity. Bolstering these intrinsic quenchers of inflammatory signal progression may offer a path to restore tissue homeostasis and repair the EB in chronic inflammatory disease states.