PMC

a Forced expression of a human α-defensin 5 (DEFA5) transgene in Paneth cells limits colonization by Salmonella enterica subsp. enterica serovar Typhimurium and controls the composition of the microbiota in the small intestine. Regenerating islet-derived protein 3γ (REG3γ) confines bacteria to the outer mucus layer, thus limiting bacterial contact with the small intestinal epithelial surface. b Cathelicidins carry out additional immunomodulatory functions in skin defence by acting on cell membrane receptors. Depending on the cell type and condition, evidence for three potential mechanisms of action exists: transactivation by antimicrobial proteins (AMPs) releases membrane-bound growth factors; AMPs bind and directly activate receptors; or AMPs activate or inactivate receptors by disrupting membrane microdomains.

a Nucleotide oligomerization domain 2 (NOD2), transcription factor 4 (TCF4), X-box-binding protein 1 (XBP1) and autophagy related 16-like 1 (ATG16L1) promote antimicrobial protein (AMP) expression and secretion by Paneth cells. Polymorphisms in the corresponding genes are associated with an increased incidence of inflammatory bowel disease^–. This could be due to compromised production of AMPs that normally control the microbiota and limit bacterial contact with the intestinal epithelial surface. b In the skin, excess production of T helper 2 (T_H2) cell cytokines is associated with atopic dermatitis, which might be owing to inhibitory effects on the induction of β-defensins. Interleukin-4 (IL-4) and IL-13 induce the expression of suppressor of cytokine signalling 1 (SOCS1) and SOCS3 through signal transducer and activator of transcription 6 (STAT6). This inhibits the action of stimulatory signals for human β-defensin 2 (BD2) and BD3 expression that are transmitted by interferon-γ (IFNγ) through STAT1, or by tumour necrosis factor (TNF) through nuclear factor-κB (NF-κB). ER, endoplasmic reticulum; MDP, muramyl dipeptide.

a The intestinal epithelium comprises several cell lineages. Enterocytes constitute the most abundant epithelial cell type, and secrete several antimicrobial proteins (AMPs) such as regenerating islet-derived protein 3γ (REG3γ). Paneth cells are unique to the small intestine and secrete abundant quantities of AMPs, such as α-defensins. Finally, goblet cells secrete mucin glycoproteins that assemble to form a thick mucus layer overlying the epithelium. The mucus layer seems to have a crucial role in concentrating secreted AMPs near the epithelial surface. b The epithelial barrier of the skin includes keratinocytes at the surface and the hair unit, and specialized secretory organs such as sebocytes and eccrine glands. Many diverse AMPs, including cathelicidins and defensins, are produced by these cells under steady-state and/or inflammatory conditions. The aqueous and lipid components of the skin surface combine with AMPs produced by microorganisms to enhance the barrier/protective function. The aqueous/lipid layer may serve a function that is similar to that of intestinal mucus by trapping AMPs at the epithelial surface. Resident bone marrow-derived cells in the dermis, such as mast cells, provide essential additional AMPs after skin injury or in early stages of infection. αMSH, α-melanocyte-stimulating hormone; ANG4, angiogenin 4; BD, β-defensin; PSM, phenol-soluble modulin; RNase7, ribonuclease 7; SLPI, secretory leukocyte protease inhibitor (also known as ALP).

a In the small intestine, the transcriptional control of α-defensin expression depends crucially on transcription factor 4 (TCF4). The pattern recognition receptor nucleotide oligomerization domain 2 (NOD2) also controls the expression and/or secretion of antimicrobial activities in the small intestinal crypt. Regenerating islet-derived protein 3γ (REG3γ) mRNA expression in enterocytes and Paneth cells is controlled by microorganism-associated molecular patterns through Toll-like receptors (TLRs) and is dependent on the TLR signalling adaptor myeloid differentiation primary response protein 88 (MYD88)^,. REG3γ mRNA expression also requires interleukin-22 (IL-22)-mediated signals from innate lymphoid cells. b In the skin, TLR2 activation can directly induce β-defensin mRNA expression but indirectly influences cathelicidin expression. The activation of MYD88 by TLR2 results in a direct transcriptional increase in cytochrome p450, 27B1 (CYP27B1) and β-defensin expression. The increased expression of CYP27B1 hydroxylates 25-OH vitamin D3 to 1,25-OH vitamin D3, and this then induces cathelicidin mRNA expression^,. β-defensins and cathelicidin released at the skin surface can function against microorganisms. Below the surface, the presence of cathelicidin peptide in the form of LL37 interacts directly with host DNA and can activate TLR9. TLR9-mediated activation of dendritic cells results in production of type I interferons (IFNα/β) and influences T helper 17 (T_H17) cell maturation and the production of IL-17, which can drive keratinocyte hyperproliferation. IL-22R, IL-22 receptor; MAMP, microbe-associated molecular pattern; MDP, muramyl dipeptide; NF-κB, nuclear factor-κB.