Role In Mucosal Host Defence Research Articles

IL-22RA1 signaling regulates intestinal secretory cell development and protects against infectious colitis

Abstract The gastrointestinal tract harbors a complex immune system to contend with both normal flora and invasive pathogens. Recently, interleukin (IL)-22 signaling has proven to play a critical role in maintaining the gut barrier, promoting epithelial healing and controlling inflammation from attaching and effacing pathogens. Specifically, IL-22 produced by Th17 cells and group 3 innate lymphoid cells (ILCs) is critical for host resistance to the attaching and effacing gut pathogen Citrobacter rodentium. However, the importance of intestinal epithelial IL-22Ra1 signaling in regulating secretory cell development and protecting against infectious colitis remains unknown. We hypothesize that intestinal IL-22 signaling plays an important role in mucosal host defense against infectious colitis by regulating the intestinal cell types that maintain the gut barrier. To test this hypothesis, we generated mice that selectively lack the receptor for IL-22, IL-22RA1, and discovered these mice have a striking phenotype of intestinal cell differentiation. We demonstrate that abrogation of intestinal IL-22 signaling led to a decreased number of goblet and paneth cells and decreased expression of the antimicrobial peptide Reg3g. Further, the IL-22RA1 intestinal specific knock-out mice were more susceptible to C. rodentium colitis than WT mice as demonstrated by increased weight loss that correlated with increased spleen bacterial burden, decreased epithelial cell proliferation and disrupted mucosal architecture. These findings offer insights into the protective role that IL-22 plays on mediating intestinal mucosal host defense and how critical IL-22 signaling is to intestinal cell differentiation and attenuating infectious colitis.

Innate immune induction and influenza protection elicited by a response-selective agonist of human C5a.

The anaphylatoxin C5a is an especially potent mediator of both local and systemic inflammation. However, C5a also plays an essential role in mucosal host defense against bacterial, viral, and fungal infection. We have developed a response-selective agonist of human C5a, termed EP67, which retains the immunoenhancing activity of C5a at the expense of its inflammatory, anaphylagenic properties. EP67 insufflation results in the rapid induction of pulmonary cytokines and chemokines. This is followed by an influx of innate immune effector cells, including neutrophils, NK cells, and dendritic cells. EP67 exhibits both prophylactic and therapeutic protection when tested in a murine model of influenza A infection. Mice treated with EP67 within a twenty-four hour window of non-lethal infection were significantly protected from influenza-induced weight loss. Furthermore, EP67 delivered twenty-four hours after lethal infection completely blocked influenza-induced mortality (0% vs. 100% survival). Since protection based on innate immune induction is not restricted to any specific pathogen, EP67 may well prove equally efficacious against a wide variety of possible viral, bacterial, and fungal pathogens. Such a strategy could be used to stop the worldwide spread of emergent respiratory diseases, including but not limited to novel strains of influenza.

Prostaglandin E2 Suppresses Antifungal Immunity by Inhibiting Interferon Regulatory Factor 4 Function and Interleukin-17 Expression in T Cells

T helper 17 (Th17) cells play an important role in mucosal host defense through production of the signature cytokines IL-17 and IL-22. Prostaglandin E2 (PGE2) has been shown to enhance IL-17 production by mature Th17 cells. However, when present during Th17 cell differentiation, we found that PGE2 inhibited the transcription factor IRF4 and suppressed production of IL-17 but not IL-22. We show that IRF4 was required for IL-17 expression but inhibited IL-22 expression, highlighting the potential for discordant regulation of these two cytokines in Th17 cells. The pathogenic fungus Cryptococcus neoformans produces PGE2, and we found that it uses PGE2- and IRF4-dependent mechanisms to specifically inhibit induction of IL-17 during Th17 cell differentiation. Blockade of host PGE2 during infection led to increased IL-17 production from CD4(+) T cells and increased survival of mice. These findings suggest that host- or pathogen-derived PGE2 can act directly on Th17 cells during differentiation to inhibit IL-17-dependent antimicrobial responses.

Antimicrobial peptides as agents of mucosal immunity.

Mucosal surfaces are continually exposed to a wide range of potentially pathogenic organisms, yet the incidence of infectious disease resulting from these encounters is relatively low. This suggests the presence of highly effective defence mechanisms in these tissues. Antimicrobial peptides have recently been discovered in mucosal tissues and may play a significant role in host defence. Several mucosal peptides (andropin, magainin, tracheal antimicrobial peptide, enteric defensins and PR-39) all fulfil minimal criteria for a role in mucosal host defence, including potent in vitro antimicrobial activity and accumulation at the mucosal surface. Most of these mucosal peptides are encoded by members of large gene families that contain members found in other biological contexts more classically associated with antimicrobial defence. The abundance, activity and evolutionary history of several epithelial peptides suggest that antimicrobial peptides play a key role in host defence at mucosal surfaces.

The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands

The endogenous anti-microbial peptide LL-37/hCAP-18 is an effector molecule of the innate host defense system at surfaces of the body. Besides its direct anti-microbial activity, the peptide interacts with different cell types. Dendritic cells (DCs) play a central role in mucosal host defense. It was the aim of the study to determine whether LL-37 modulates the response of DCs to pathogen-associated molecular patterns. Monocyte-derived DCs were stimulated with the Toll-like receptors (TLRs) ligands LPS, lipoteichoic acid and flagellin. We measured classical markers of DC maturation and assayed the ability of the DCs to activate T cell responses. Co-incubation with LL-37 resulted in suppressed activation of DCs. Levels of released IL-6, IL-12p70 and TNF-alpha and surface expression of HLA-DR, CD80, CD83, CD86 and the chemokine receptor CCR7 were decreased. Exposure of DCs to LL-37 during LPS exposure induced co-cultured naive T cells to produce less IL-2 and IFN-gamma and decreased their proliferation. The response of memory T cells to a recall antigen was also decreased. In conclusion, we demonstrate that the anti-microbial peptide LL-37 inhibits the activation of DCs by TLR ligands. We propose that LL-37 is a regulator of host defense responses at the intersection of innate and adaptive immune systems.

Nasal-associated lymphoid tissue (NALT): frequency and localization in young children.

In mucosal immunology nasal-associated lymphoid tissue (NALT) is taken as a constitutive structure of the nasal immune system and as a target tissue in strategies of local defence and an induction site for vaccination. These concepts are based on findings in rodents, but it has not been investigated systematically whether NALT also is present in humans and if so in which amount and localization. In a postmortem study the presence of NALT in humans is documented as a morphologically distinct structure additional to the lymphoid structures of the Waldeyer's ring. Human nasal tissue blocks of 150 children who had died in the first two years of life either of sudden infant death (n = 109) without signs of respiratory tract infections or of different traumatic (n = 22) and natural causes of death (n = 19) were obtained using a specific autopsy-technique and were investigated systematically using histology. Clearly in contrast to rodents human NALT was found disseminated in the nasal mucosa with typical morphological features in 38% of all children, mainly in the middle concha, with similar morphology and frequency in the examined groups. No correlation was found between the presence of NALT and the cause of death and especially the grade of inflammation in general. Therefore, NALT might be the morphological basis for inhalative vaccination strategies in young children and play a role in mucosal host defence.

Hyaluronan serves a novel role in airway mucosal host defense.

Enzymes secreted onto epithelial surfaces play a vital role in innate mucosal defense, but are believed to be steadily removed from the surface by mechanical actions. Thus, the amount and availability of enzymes on the surface are thought to be maintained by secretion. In contrast to this paradigm, we show here that enzymes are retained at the apical surface of the airway epithelium by binding to surface-associated hyaluronan, providing an apical enzyme pool 'ready for use' and protected from ciliary clearance. We have studied lactoperoxidase, which prevents bacterial colonization of the airway, and kallikrein, which mediates allergic bronchoconstriction that limits the inhalation of noxious substances. Binding to hyaluronan inhibits kallikrein, which is needed only in certain situations, whereas lactoperoxidase, useful at all times, does not change its activity. Hyaluronan itself interacts withthe receptor for hyaluronic acid-mediated motility (RHAMM or CD168) that is expressed at the apex of ciliated airway epithelial cells. Functionally, hyaluronan binding to RHAMM stimulates ciliary beating. Thus, hyaluronan plays a previously unrecognized pivotal role in mucosal host defense by stimulating ciliary clearance of foreign material while simultaneously retaining enzymes important for homeostasis at the apical surface so that they cannot be removed by ciliary action.