Development of atopic dermatitis-like skin disease from the chronic loss of epidermal caspase-8

Abstract

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

Apoptotic and Nonapoptotic Caspase Functions in Animal Development

“…Caspase-8's importance is supported by the observation that caspase-8-deficient skin shows epidermal hyperplasia (Lee et al 2009b). The chronic loss of epidermal caspase-8 in mice enhances wound-healing responses and recapitulates atopic dermatitis (Li et al 2010a). Consistent with this, caspase-8 is increased in diabetic mice in which wound healing is impaired (Al-Mashat et al 2006).…”

Caspase Functions in Cell Death and Disease

“…Apaf1 2/2 cells cannot activate caspases in response to mitochondrial pathway stimulation, are resistant to many apoptotic stimuli, and display reduced processing of caspases-2, -3, and -8 (Yoshida et al 1998). Are more susceptible to virus infection ); show enhanced tumor formation (Hu et al 2010); have reduced apoptosis in several models such as neuronal cell death, myocardiac infarct, and heart failure (Frantz et al 2003;Arai et al 2006;Merkle et al 2007); caspase-1-deficient mice are protected against cisplatininduced apoptosis and acute tubular necrosis (Faubel et al 2004) Kuida et al 1995;Li et al 1995;Thomas et al 2009;Hu et al 2010 Caspase Juo et al 1998;Varfolomeev et al 1998;Chun et al 2002;Salmena et al 2003;Kang et al 2004;Beisner et al 2005;Kovalenko et al 2009;Lee et al 2009a;Li et al 2010;Kaiser et al 2011;Zhang et al 2011 Caspase-9 Perinatal lethal, but not 100% penetrant…”

“…However, tissue-specific deletions of caspase-8 have revealed new roles for this caspase, which appear to be unrelated to apoptosis. Caspase-8 function is also critical for T-cell homeostasis (Salmena et al 2003), the generation of myeloid and lymphoid cells and macrophage differentiation (Kang et al 2004;Beisner et al 2005), and skin inflammation and wound healing (Kovalenko et al 2009;Lee et al 2009a;Li et al 2010). Recently, three reports provided evidence that some of the defects associated with loss of caspase-8, and result in embryonic death, are not owing to impaired apoptosis but rather to defective suppression of receptor-interacting serinethreonine kinase 3 (RIPK3) -dependent necrosis (Kaiser et al 2011;Zhang et al 2011).…”

When Beauty Is Skin Deep: Regulation of the Wound Response by Caspase-8, RIPK3, and the Inflammasome

“…Similar to these findings, in this issue (Lee et al, 2015), work from the Jamora laboratory demonstrates that an in vitro scratch "wound" ablates caspase-8 protein expression in keratinocytes at the scratch edge and that this correlates directly with increased NF-κB activation and caspase-1 levels. Consistent with these observations being physiologically important, reduced caspase-8 or its mutation is associated with atopic dermatitis (Chun et al, 2002;Li et al, 2010), and keratinocyte-specific deletion of murine caspase-8, or its essential adaptor protein FADD, triggers chronic inflammatory skin disease and the upregulation of many genes induced during epidermal wound healing (Kovalenko et al, 2009;Lee et al, 2009;Li et al, 2010;Bonnet et al, 2011).…”