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Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood–brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions. Although it is known that microglia respond to injury and systemic disease in the brain, it is unclear if they modulate blood–brain barrier (BBB) integrity, which is critical for regulating neuroinflammatory responses. Here authors demonstrate that microglia respond to inflammation by migrating towards and accumulating around cerebral vessels, where they initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 before switching, during sustained inflammation, to phagocytically remove astrocytic end-feet resulting in impaired BBB function

The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases.

ABSTRACTThe choroid plexus (CP) is considered to be a point of leukocyte entry into the CNS during normal immune surveillance and in neuroinflammatory diseases. The structural and functional alterations within the CP that support this migration are not understood. We used quantitative, high-resolution, 3-dimensional (3-D) fluorescence imaging to analyze CP alterations associated with inflammatory responses in C57/Bl6 mice after the induction of experimental autoimmune encephalomyelitis by immunization with myelin oligodendrocyte glycoprotein (MOG) and complete Freund adjuvant/pertussis toxin (MOG-CFA/PTX) or adjuvants alone (CFA-PTX). The MOG-CFA/PTX and CFA/PTX produced similar effects, although those caused by the former were consistently more marked. Both treatments resulted in the accumulation of serum immunoglobulin G and leukocytes in the CP stroma, consistent with elevated stromal capillary permeability. They also provoked distortions and diminished immunostaining patterns of the tight junction adaptor protein ZO-1 in the choroidal epithelium but no obvious change in the patterns of the tight junction associated protein claudin-2. Only MOG-CFA/PTX triggered visible extravasation of immunoglobulin G and leukocytes across the choroidal epithelium. Our results suggest that CFA/PTX primes the CP for neuroinflammation by inducing structural changes that are exacerbated when there is an immune response to MOG and reinforce the CP as a gateway for leukocytes to enter the CNS by accessing the CSF and leptomeninges.

The intestine is a unique organ inhabited by a tremendous number of microorganisms. Intestinal epithelial cells greatly contribute to the maintenance of the symbiotic relationship between gut microbiota and the host by constructing mucosal barriers, secreting various immunological mediators and delivering bacterial antigens. Mucosal barriers, including physical barriers and chemical barriers, spatially segregate gut microbiota and the host immune system to avoid unnecessary immune responses to gut microbes, leading to the intestinal inflammation. In addition, various immunological mediators, including cytokines and chemokines, secreted from intestinal epithelial cells stimulated by gut microbiota modulate host immune responses, maintaining a well-balanced relationship between gut microbes and the host immune system. Therefore, impairment of the innate immune functions of intestinal epithelial cells is associated with intestinal inflammation. Gut immunology: The importance of epithelial middle-men A review by researchers in Japan highlights how gut epithelial cells moderate interactions between foreign microbes and the immune system. Epithelial cells line the surface of the gut, separating the body's immune system from the gut microbes that enter the body with food. Drawing on numerous recent studies, Ryu Okamura and Kiyoshi Takeda at Osaka University identify two main roles that epithelial cells perform to maintain a healthy balance in the gut. Firstly, the cells segregate gut microbes from the immune system by constructing physical and chemical barriers. Secondly, they mediate interactions by passing information between the microbes and the immune system, triggering immune responses where necessary. Understanding the role of these cells is important given increasing evidence that defects in their functions are strongly related to inflammatory bowel problems such as ulecerative colitis.

Macrophages are a heterogeneous group of cells that are capable of carrying out distinct functions in different tissues, as well as in different locations within a given tissue. Some of these tissue macrophages lie on, or close to, the outer (abluminal) surface of blood vessels and perform several crucial activities at this interface between the tissue and the blood. In steady-state tissues, these perivascular macrophages maintain tight junctions between endothelial cells and limit vessel permeability, phagocytose potential pathogens before they enter tissues from the blood and restrict inappropriate inflammation. They also have a multifaceted role in diseases such as cancer, Alzheimer disease, multiple sclerosis and type 1 diabetes. Here, we examine the important functions of perivascular macrophages in various adult tissues and describe how these functions are perturbed in a broad array of pathological conditions.

Key Points T helper 17 (T H 17) cells activated by transforming growth factor-β (TGFβ) and interleukin-6 (IL-6) promote mucosal defence, barrier tissue integrity and curtail immunopathogenic responses, whereas IL-23-activated T H 17 cells promote chronic tissue inflammation during infection, granuloma formation and autoimmunity. Retinoic acid receptor-related orphan receptor-γt (RORγt) is a T H 17 cell-specific master transcription factor. However, it does not act alone, but instead functions as part of a protein complex that regulates T H 17 lineage fate. RORγt takes advantage of the open DNA conformation induced by basic leucine zipper transcription factor ATF-like (BATF) and interferon-regulatory factor 4 (IRF4) following T cell receptor stimulation. RORγt also requires the presence of inflammatory cytokine-induced signal transducer and activator of transcription 3 (STAT3) and, together, these transcription factors function as a 'rheostat' that fine-tunes a pre-established T H 17 lineage programme. IL-17 signalling is mediated through a distinct cytokine receptor family, which is characterized by a conserved SEF/IL-17R (SEFIR) domain in the cytoplasmic tail. All known IL-17-dependent signalling events occur through ACT1, which controls TNF receptor-associated factor (TRAF)-dependent activation of downstream signalling components (for example, mitogen-activated protein kinases) and transcription factors (for example, nuclear factor-κB (NF-κB) and CCAAT/enhancer-binding proteins (C/EBPs) and mRNA stability. IL-17 signal transduction is restricted by multiple downstream events, involving inhibitory transcription factors, ubiquitylation/deubiquitylation of signalling intermediates, microRNA regulation and control of target mRNA stability. In vivo , IL-17 is an essential regulator of immunity to fungi, particularly the commensal fungus Candida albicans . Humans with congenic or acquired blockade of the IL-17 signalling pathway are particularly susceptible to chronic mucosal candidiasis. The therapeutic strategy of targeting IL-17 and IL-23 shows encouraging results for psoriasis, Crohn's disease, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. T helper 17 (T H 17) cells promote protective immune responses against infection, particularly at barrier sites, but they can also have pathogenic roles in inflammatory diseases. In this Review, the authors describe the factors that control the development and maintenance of T H 17 cells, and discuss their diverse functions in both health and disease. Following the discovery of T helper 17 (T H 17) cells, the past decade has witnessed a major revision of the T H subset paradigm and substantial progress has been made in deciphering the molecular mechanisms of T cell lineage commitment and function. In this Review, we focus on the recent advances that have been made regarding the transcriptional control of T H 17 cell plasticity and stability, as well as the effector functions of T H 17 cells, and we highlight the mechanisms of IL-17 signalling in mesenchymal and barrier epithelial tissues. We also discuss the emerging clinical data showing that IL-17-specific and IL-23-specific antibody treatments are remarkably effective for treating many immune-mediated inflammatory diseases.

Background Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene–environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD. Methods Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated. Results Claudin ( CLDN )-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3 , tricellulin , and MMP-9 were higher in the ASD cortex. IL-8 , tPA , and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components ( CLDN-1 , OCLN , TRIC ), whereas 66% had increased pore-forming CLDNs ( CLDN-2 , -10 , -15 ) compared to controls. Conclusions In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

Key Points Mucosal barrier function consists of the combined effects of multiple extracellular and cellular processes that may be disrupted globally or in a targeted manner by physiological and pathophysiological stimuli. In the presence of an intact epithelium, mucosal permeability is primarily determined by tight junction barrier function. Intestinal epithelial cells mediate interactions between the mucosal immune system and luminal materials. The mechanisms by which these epithelia regulate and, conversely, are regulated by the immune system are therefore of crucial importance to mucosal homeostasis and disease. In vitro and in vivo studies have indicated that cytokines, including tumour necrosis factor, LIGHT (also known as TNFSF14), interferon-γ, interleukin-13 (IL-13) and IL-17 can modify epithelial barrier function by mechanisms that include new protein synthesis, membrane trafficking, kinase activation, cytoskeletal modulation and epithelial apoptosis. The contributions of these events to acute and chronic barrier regulation are distinct and may complement one another. Increased intestinal permeability is associated with inflammatory bowel disease but can also be present in healthy individuals. Mouse models confirm that intestinal barrier dysregulation alone is insufficient to cause disease, but they also show that enhanced tight junction permeability can accelerate disease onset and increase severity. In addition to activating pro-inflammatory events, intestinal barrier dysfunction initiates immunoregulatory processes. Defects in these processes may be a cause of inflammatory disease. Further investigation of pathways that integrate mucosal barrier function, or dysfunction, and immune regulation will lead to a better understanding of the mechanisms underlying these complex interactions and provide a rational basis for the development of more effective and targeted therapeutic interventions. Mucosal surfaces are lined by epithelial cells that establish a barrier between external environments and the internal milieu. Recent advances have uncovered mechanisms of barrier regulation by immune stimuli and, conversely, how mucosal immunity is regulated by barrier function. Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. Here I discuss these discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.

IL-18 is emerging as an IL-22-induced and epithelium-derived cytokine which contributes to host defence against intestinal infection and inflammation. In contrast to its known role in Goblet cells, regulation of barrier function at the molecular level by IL-18 is much less explored. Here we show that IL-18 is a bona fide IL-22-regulated gate keeper for intestinal epithelial barrier. IL-22 promotes crypt immunity both via induction of phospho-Stat3 binding to the Il-18 gene promoter and via Il-18 independent mechanisms. In organoid culture, while IL-22 primarily increases organoid size and inhibits expression of stem cell genes, IL-18 preferentially promotes organoid budding and induces signature genes of Lgr5 + stem cells via Akt-Tcf4 signalling. During adherent-invasive E. coli (AIEC) infection, systemic administration of IL-18 corrects compromised T-cell IFNγ production and restores Lysozyme + Paneth cells in Il-22 −/− mice, but IL-22 administration fails to restore these parameters in Il-18 −/− mice, thereby placing IL-22-Stat3 signalling upstream of the IL-18-mediated barrier defence function. IL-18 in return regulates Stat3-mediated anti-microbial response in Paneth cells, Akt-Tcf4-triggered expansion of Lgr5 + stem cells to facilitate tissue repair, and AIEC clearance by promoting IFNγ + T cells. IL-22 induces IL-18 expression by intestinal epithelial cells. Authors show here that IL-18 is a key barrier maintenance factor during adherent-invasive E. coli invasion, inducing expression of anti-microbial genes in Paneth cells via Stat3, prompting IFNγ expression in T cells and triggering intestinal Lgr5 + stem cell expansion via Tcf4.

The nature and role of the intestinal leukocytes in necrotizing enterocolitis (NEC), a severe disease affecting premature infants, remain unknown. We now show that the intestine in mouse and human NEC is rich in lymphocytes that are required for NEC development, as recombination activating gene 1–deficient (Rag1–/–) mice were protected from NEC and transfer of intestinal lymphocytes from NEC mice into naive mice induced intestinal inflammation. The intestinal expression of the lipopolysaccharide receptor TLR4, which is higher in the premature compared with full-term human and mouse intestine, is required for lymphocyte influx through TLR4-mediated upregulation of CCR9/CCL25 signaling. TLR4 also mediates a STAT3-dependent polarization toward increased proinflammatory CD3+CD4+IL-17+ and reduced tolerogenic Foxp3+ Treg lymphocytes (Tregs). Th17 lymphocytes were required for NEC development, as inhibition of STAT3 or IL-17 receptor signaling attenuated NEC in mice, while IL-17 release impaired enterocyte tight junctions, increased enterocyte apoptosis, and reduced enterocyte proliferation, leading to NEC. Importantly, TLR4-dependent Th17 polarization could be reversed by the enteral administration of retinoic acid, which induced Tregs and decreased NEC severity. These findings identify an important role for proinflammatory lymphocytes in NEC development via intestinal epithelial TLR4 that could be reversed through dietary modification.