https://www.cell.com/trends/immunology/pdf/S1471-4906(09)00005-2.pdf

AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense

Surface tissues of the body such as the skin and intestinal tract are in direct contact with the external environment and are thus continuously exposed to large numbers of microorganisms. To cope with the substantial microbial exposure, epithelial surfaces produce a diverse arsenal of antimicrobial proteins that directly kill or inhibit the growth of microorganisms. In this Review, we highlight new advances in our understanding of how epithelial antimicrobial proteins protect against pathogens and contribute to microbiota-host homeostasis at the skin and gut mucosae. Further, we discuss recent insights into the regulatory mechanisms that control antimicrobial protein expression. Finally, we consider how impaired antimicrobial protein expression and function can contribute to disease.

Epithelial antimicrobial defence of the skin and intestine

A comprehensive summary of LL-37, the factotum human cathelicidin peptide

1.1. General overview
The strategic location of the skin as the barrier between the environment and internal milieu determines its critical function in the preservation of body homeostasis, and ultimately organism survival (Slominski, 2005, Slominski and Wortsman, 2000, Slominski et al., 2000c, Zmijewski and Slominski, 2011). It also exposes skin to numerous pathological agents, processes, and events. Thus, the capability to locally recognize, discriminate and integrate various signals within a highly heterogeneous environment, and to immediately launch appropriate responses, is a vital property of skin (Slominski and Wortsman, 2000). These skin functions are integrated into the skin immune, pigmentary, epidermal and adnexal systems, and are in continuous communication with the systemic immune, neural and endocrine systems (Arck et al., 2006, Slominski, 2009c, Slominski et al., 2004c, Slominski and Wortsman, 2000, Slominski et al., 2007a, Stenn and Paus, 2001).

These fundamental functions results from the location of the skin, which is the largest body’s organ, at the interphase between external and internal environment, requiring development of efficient sensory and effector capabilities to differentially react to changes in external environment. They are represented by inducible production of biologically active compounds (hormones, neurohormones and neurotransmitters) that act both locally and at the systemic levels (Fig. 1).



Figure 1

Skin senses changes in the environment through cutaneous neuroendocrine system, which computes and translates the received information into chemical, physical and biological messengers that regulate global (A and B) and local (B) homeostasis. These signals ...



The skin being continuously exposed to many external biological or environmental factors (acute transfers of solar, thermal or chemical energy), had to evolve optimal mechanism(s) to protect, restore or maintain local and global homeostasis in relation to hostile environment (Slominski et al., 1993b, Slominski and Pawelek, 1998, Slominski and Wortsman, 2000, Slominski et al., 2000c). We have proposed that precise coordination and execution of these responses are mediated by a cutaneous neuroendocrine system, which also is able to reset the body homeostatic adaptation mechanisms (Slominski and Wortsman, 2000). Superimposed on this is the impact of psychological stress on skin physiology and pathology, placed in the context of the bidirectional brain-skin communication (Arck et al., 2006, Slominski, 2005a, Slominski et al., 2008b). To summarize, in reaction to changing external and also internal environment, the skin can generate signals to produce rapid (neural) or slow (humoral or immune) responses at the local and systemic levels (Fig. 1).

Coordination between these local and systemic responses is mediated by the skin neuroendocrine system (Slominski and Wortsman, 2000a), which employs local equivalents of the hypothalamo-pituitary-adrenal axis (HPA) (Slominski et al., 2007a), hypothalamo-pituitary-thyroid (HPT) axis (Pisarchik and Slominski, 2002, van Beek et al., 2008), catecholaminergic (Schallreuter et al., 1997), serotoninergic, melatoninergic (Slominski et al., 2008a, Slominski et al., 2005c), cholinergic (Grando, 2006, Grando et al., 2006), steroidogenic (Slominski et al., 2008b) and secosteroidogenic (Bikle, 2010, Holick, 2003, Slominski et al., 2010) systems (Fig. 2). Given their common embryonic origins, it is not surprising that skin shares numerous mediators with the CNS and endocrine system. Recent research has revealed that skin also harbors a complex opioidogenic (Grando et al., 1995, Slominski et al., 2011c) and canabinnoidogenic (Biro et al., 2009) systems, which role in the maintenance of cutaneous homeostasis is currently being intensively explored.



Figure 2

Skin neuroendocrine system follows the algorithms of classical neuroendocrine or endocrine systems. It also forms a natural platform of signal exchange between internal organs and environment. For this purpose skin cells not only are subjected to neurohormonal ...



In this monograph we will discuss the role of various components of the skin neuroendocrine system in sensing the environment with subsequent regulation of local and global homeostasis with a main focus on the algorithms of classical neuroendocrine axes.

Sensing the Environment: Regulation of Local and Global Homeostasis by the Skin's Neuroendocrine System

Until quite recently, the pathogenesis of atopic dermatitis (AD) has been attributed to primary abnormalities of the immune system. Intensive study revealed the key roles played by TH1/TH2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the evolution of the chronic, pruritic, inflammatory dermatosis that characterizes AD. Accordingly, current therapy has been largely directed toward ameliorating TH2-mediated inflammation and pruritus. In this review we will assess emerging evidence that inflammation in AD results from inherited and acquired insults to the barrier and the therapeutic implications of this paradigm.

Basis for the barrier abnormality in atopic dermatitis: Outside-inside-outside pathogenic mechanisms

Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers.

Carbohydrate antigen 19-9 (CA 19-9) is a commonly used tumor marker for pancreatic cancer. However, CA 19-9 can be overexpressed in several benign inflammatory diseases. We investigated the relationship between high CA 19-9 level and low muscle mass (LMM) in healthy adults without cancer. Participants who underwent evaluation of muscle mass and CA 19-9 were included. Exclusion criteria were any malignancy, cardiovascular disease, tuberculosis, and chronic lung/liver disease. Participants were classified into “normal”, “mild LMM”, and “severe LMM” groups based on the skeletal muscle mass index. Multivariable logistic regression analyses were conducted to assess the association of high CA 19-9 with muscle mass status. A total of 263,061 adults were included. The mean age and SMI were 41.03 years and 7.13 kg/m2. After adjustments for various confounders, high CA 19-9 was independently associated with mild LMM (adjusted odds ratio, 1.677 [95% confidence interval, 1.533–1.834]) and severe LMM (2.651 [2.126–3.306]) compared to the normal group. Furthermore, the association between high CA 19-9 and severe LMM was stronger in men than in women. Elevated CA 19-9 levels were independently associated with a higher prevalence of LMM in healthy adults without cancer. Therefore, increased CA 19-9 could be utilized as a novel biomarker for sarcopenia. 

The Association of Carbohydrate Antigen (CA) 19-9 Levels and Low Skeletal Muscle Mass in Healthy Adults

Jin-Woo Suh, M.D., Han-Sol Lim, M.D., Dong-Kun Kim, M.D., Hyun Seung Lee, M.D., Yong-Taek Lee, M.D., Ph.D., Young Sook Park, M.D., Ph.D., Chul-Hyun Park, M.D., Ph.D., Kyung-Jae Yoon, M.D., Ph.D.. J Korean Dysphagia Soc 2022;12:115-22. https://doi.org/10.34160/jkds.2022.12.2.005 

Natural Course of Swallowing Recovery and Associated Factors in Post-Ischemic Stroke Dysphagia

The skin is the first line of defense against microbial infection, and psychological stress (PS) has been shown to have adverse effects on cutaneous barrier function. Here we show that PS increased the severity of group A Streptococcus pyogenes (GAS) cutaneous skin infection in mice; this was accompanied by increased production of endogenous glucocorticoids (GCs), which inhibited epidermal lipid synthesis and decreased lamellar body (LB) secretion. LBs encapsulate antimicrobial peptides (AMPs), and PS or systemic or topical GC administration downregulated epidermal expression of murine AMPs cathelin-related AMP and β-defensin 3. Pharmacological blockade of the stress hormone corticotrophin-releasing factor or of peripheral GC action, as well as topical administration of physiologic lipids, normalized epidermal AMP levels and delivery to LBs and decreased the severity of GAS infection during PS. Our results show that PS decreases the levels of 2 key AMPs in the epidermis and their delivery into LBs and that this is attributable to increased endogenous GC production. These data suggest that GC blockade and/or topical lipid administration could normalize cutaneous antimicrobial defense during PS or GC increase. We believe this to be the first mechanistic link between PS and increased susceptibility to infection by microbial pathogens.

/pdf/psychological-stress-downregulates-epidermal-antimicrobial-3gmm6aqbap.pdf

Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice

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Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers.

The Association of Carbohydrate Antigen (CA) 19-9 Levels and Low Skeletal Muscle Mass in Healthy Adults

Natural Course of Swallowing Recovery and Associated Factors in Post-Ischemic Stroke Dysphagia

Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice