The Dichotomous Responses Driven by β-Defensins

Abstract

Defensins are short, rapidly evolving, cationic antimicrobial host defence peptides with a repertoire of functions, still incompletely realised, that extends beyond direct microbial killing. They are released or secreted at epithelial surfaces, and in some cases, from immune cells in response to infection and inflammation. Defensins have been described as endogenous alarmins, alerting the body to danger and responding to inflammatory signals by promoting both local innate and adaptive systemic immune responses. However, there is now increasing evidence that they exert variable control on the response to danger; creating a dichotomous response that can suppress inflammation in some circumstances but exacerbate the response to danger and damage in others and, at higher levels, lead to a cytotoxic effect. Focussing in this review on human β-defensins, we discuss the evidence for their functions as proinflammatory, immune activators amplifying the response to infection or damage signals and/or as mediators of resolution of damage, contributing to a return to homeostasis. Finally, we consider their involvement in the development of autoimmune diseases.

Keywords: AMP; atopic dermatitis; autoimmunity; beta defensin; immunomodulation; psoriasis.

Figure 1

The many roles of β-defensins. β-defensins have been shown to have a wide range of roles, that go far beyond basic antimicrobial activity. These can loosely be grouped into five key groups; triggering and enhancing, chemoattraction (chemoattractive), neutral antagonist, non-resolving and resolving. These functions are represented here, alongside the most prominent cell types/tissues/organisms associated with that particular role. Particular receptors that are known be involved in these pathways have also been highlighted, alongside the consequence of the β-defensin stimulus. These have also been grouped into pro-inflammatory or anti-inflammatory (or neither). Abbreviations: interferon (IFN), toll like receptor (TLR), Dendritic Cell (DC), interleukin (IL), T helper (Th), regulatory B cell (Breg). β-defensin structure taken from PBD reference 1kj6 (44).

Figure 2

The possible implications for β-defensins in psoriasis. Psoriasis is a disease characterised by scaly lesions, hyperplastic epidermal thickening, immune cell accumulation and is triggered by some sort of insult to the skin. HBD2 and 3 may contribute to the disease process as a consequence of increased gene copy number increasing the level of the peptide response to inflammation and enhancing monocyte/macrophage recruitment and increasing uptake of nucleic acids released from dying cells or microbes at the site of damage. Shown here is increased dsRNA entering macrophages with β-defensin and enhancing IFNβ secretion leading to Langerhan cell maturation and interleukin (IL)-23 release to influence mature T cell polarisation to T helper (Th)17. IL-22 production from Th17 may then further stimulate β-defensin production and amplify the process. Abbreviations: Copy number (CN), C-C chemokine receptor type 2 (CCR2), interleukin (IL), melanoma differentiation-associated protein 5 (MDA5), T helper (Th).

Figure 3

The possible implications for β-defensins in atopic dermatitis. Atopic dermatitis (AD) is a chronic, relapsing disease associated with itchy lesions on the skin, across a large proportion of the body. These lesions are characterised by a breakdown in the barrier function of the uppermost regions of the skin (the epidermis). This allows for an increase in bacterial infection, which is made worse by bacterial production of proteases that further breakdown the junctions between cells, as is the case for V8 (SspA) production by Staphylococcus aureus. In AD, there is a downregulation in a number of Th1-associated cytokines, such as Tumour Necrosis Factor (TNF)α and interleukin (IL)-1β, as well as antimicrobial peptides, such as the β-defensins (including HBD2). It is thought that the AD-associated, localised cytokine milieu, which has a T helper (Th)2-skewed phenotype, is responsible for this reduction. Inhibition of the induction of β-defensins prevents proper bacterial removal/inhibition, worsening infection and AD pathology. Abbreviations: interleukin (IL), Toll Like Receptor (TLR), pathogen recognition receptor (PRR).