Hematopoietic plakophilin‐3 regulates acute tissue‐specific and systemic inflammation in mice

Abstract

Plakophilin-3 (PKP3) is a member of the armadillo protein family, which is important inKeywords: Acute inflammation r Colitis r Dermatitis r Hematopoietic cell r Intestine r Plakophilin-3 r Sepsis r SkinAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe interaction of the organism with its environment requires the presence of a specialized "danger sensing" system. This protective system operates mostly at the surfaces between the outer and inner environments of the body, such as the skin, intestinal tract, and respiratory tract. From a classical point of view, the epithelial Correspondence: Mrs. Roosmarijn E. Vandenbroucke e-mail: Roosmarijn.Vandenbroucke@irc.VIB-UGent.be surfaces at these locations form a physical barrier that is impermeable to most infectious agents and thereby provide a first line of defense. More recently, subtle interactions between microbes and these epithelial surfaces have been shown to determine local immune reactions and disease. The barriers consists of three parts: an extensive epithelial cell surface exposed to the environment, a basement membrane that, together with various cell-junction structures, provides an extra level of separation, and a highly reactive lymphoid tissue underneath composed of antigen-presenting cells [1][2][3][4].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2898-2910 Innate immunity 2899Several inflammatory conditions, such as skin inflammation, inflammatory bowel disease (IBD) and the systemic inflammatory response syndrome (SIRS), are associated with disruption of the respective epithelial barriers. The skin is the largest organ of the body and is continuously exposed to microorganisms, ultraviolet radiation, toxic agents, and mechanical stress. Skin inflammation can be mimicked in the mouse by topical application of a single dose of 12-O-tetradecanoylphorbol-13-acetate, also known as phorbol-12-myristate-13-acetate (PMA). This induces an acute inflammatory reaction called irritant contact dermatitis (ICD) consisting of erythema, edema, and polymorphonuclear leukocyte (PMN) infiltration [5]. Skin inflammation is accompanied by epidermal barrier disruption because tight junctions between keratinocytes are disrupted and cytokines induce apoptosis or necrosis of keratinocytes [6]. Disruption of the epithelial barrier is also a key feature of IBD [7,8]. The intestinal barrier defects activate the underlying immune system, resulting in tissue damage. The dextran sulfate sodium (DSS) model of colitis correlates well with human IBD and is deemed suitable for investigating its pathogenesis [9]. SIRS is a lethal inflammatory disease caused by trauma, burns, infections, and other insults [10]. When SIRS is associated with hypotension, it is known as sepsis or septic shock. Several mouse models of sepsis are known [10]. The endotoxemia model involves the injection of bacterial lipopolysaccharides (LPS), which binds to the pathogen-recognition...

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