Atopic dermatitis is an inflammatory skin disease that affects approximately 20% of children worldwide. Left untreated, the barrier function of the skin is compromised, increasing susceptibility to dehydration and infection. Despite its prevalence, its multifactorial nature has complicated the unraveling of its etiology. We found that chronic loss of epidermal caspase-8 recapitulates many aspects of atopic dermatitis, including a spongiotic phenotype whereby intercellular adhesion between epidermal keratinocytes is disrupted, adversely affecting tissue architecture and function. Although spongiosis is generally thought to be secondary to edema, we found that suppression of matrix metalloproteinase-2 activity is sufficient to abrogate this defect. p38 MAPK induces matrix metalloproteinase-2 expression to cleave Ecadherin, which mediates keratinocyte cohesion in the epidermis. Thus, the conditional loss of caspase-8, which we previously found to mimic a wound response, can be used to gain insights into how these same wound-healing processes are commandeered in inflammatory skin diseases.inflammation | adherens junction | T cells | eczema
The inflammasome is a complex of proteins that plays a critical role in mounting an inflammatory response in reply to a harmful stimulus that compromises the homeostatic state of the tissue. The NLRP3 inflammasome, which is found in a wound-like environment, is comprised of three components: the NLRP3, the adaptor protein ASC and caspase-1. Interestingly, while ASC levels do not fluctuate, caspase-1 levels are elevated in both physiological and pathological conditions. Despite the observation that merely raising caspase-1 levels is sufficient to induce inflammation, the crucial question regarding the mechanism governing its expression is unexplored. We find that in an inflammatory microenvironment, caspase-1 is regulated by NFκB. Consistent with this association, the inhibition of caspase-1 activity parallels the effects on wound-healing caused by the abrogation of NFκB activation. Surprisingly, not only does inhibition of the NFκB/caspase-1 axis disrupt the inflammatory phase of the wound-healing program, it also impairs the stimulation of cutaneous epithelial stem cells of the proliferative phase. These data provide a mechanistic basis for the complex interplay between different phases of the wound-healing response in which the downstream signaling activity of immune cells can kindle the amplification of local stem cells to advance tissue repair.
Vascular flow through tissues is regulated via a number of homeostatic mechanisms. Localized control of tissue blood flow, or autoregulation, is a key factor in regulating tissue perfusion and oxygenation. We show here that the net balance between two hypoxia-inducible factor (HIF) transcription factor isoforms, HIF-1α and HIF-2α, is an essential mechanism regulating both local and systemic blood flow in the skin of mice. We also show that balance of HIF isoforms in keratinocyte-specific mutant mice affects thermal adaptation, exercise capacity, and systemic arterial pressure. The two primary HIF isoforms achieve these effects in opposing ways that are associated with HIF isoform regulation of nitric oxide production. We also show that a correlation exists between altered levels of HIF isoforms in the skin and the degree of idiopathic hypertension in human subjects. Thus, the balance between HIF-1α and HIF-2α expression in keratinocytes is a control element of both tissue perfusion and systemic arterial pressure, with potential implications in human hypertension.HIF-alpha | arginase | vascular tone A utoregulation of vascular flow in peripheral tissues is essential both for controlling local tissue perfusion and for the regulation of systemic blood pressure. This dual role for peripheral blood flow is dependent in turn on a range of factors that act to adjust local vascular tone. A key element of this control is the balance between O 2 demand and O 2 supply (1). This balance causes increased need for oxygen to induce increased blood flow. This regulatory pathway in peripheral tissues has a direct impact on systemic arterial pressure, because peripheral vascular resistance in large part determines total vascular resistance in the arterial bed.The skin contains a very extensive series of vascular plexi. This vascular bed has a range of essential functions, which include regulating body temperature. Skin circulation also is altered in a number of disease states, including renal disease (2), hypercholesterolemia (3), peripheral vascular disease (4), heart failure, and hypertension (5). Identification of structural alterations to the subcutaneous microvasculature provides a powerful prognostic tool to predict cardiovascular events in hypertensive patients (6), and impaired microvascular vasodilation and capillary rarefaction is associated with familial predisposition to hypertension (7).The heterodimeric transcription factors hypoxia-inducible factoralpha (HIF-1α) and HIF-2α are essential for the maintenance of cellular oxygen homeostasis (8). In response to hypoxia, stabilized HIF-1α and HIF-2α proteins initiate the expression of genes that alleviate hypoxic stress, including genes promoting cell growth, adhesion, and migration, new vessel formation, and the development of vascular networks (9,10).Recent data from a number of groups have indicated that HIF-1α and HIF-2α can act in a dualistic manner to regulate a range of responses in vivo; these interactions include functionally opposing interactions with the Myc t...
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