Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux

Aim

This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX).

Methods

We assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH_i of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR.

Results

CAIX‐knockout gastric surface epithelial cells showed significantly faster pH_i decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months.

Conclusions

We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO₂ and H₂O, contributing to tight junction protection and gastric epithelial pH_i regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.     

Ionoregulatory and oxidative stress issues associated with the evolution of air-breathing

Aquatic areas frequently face hypoxic conditions. In order to get sufficient oxygen to support aerobic metabolism, a number of freshwater fish resort to aerial respiration to supplement gill respiration especially in situations with reduced oxygen availability in the water. In many species a concomitant reduction in gill surface area or in gill perfusion reduces possible loss of aerially acquired oxygen to the water at the gills, but it also compromises the ion regulatory capacity of gill tissue. In consequence, the reduced gill contact area with water requires appropriate compensation to maintain ion and acid-base homeostasis, often with important ramifications for other organs. Associated modifications in the structure and function of the gills themselves, the skin, the gut, the kidney, and the physiology of water exchange and ion-linked acid-base regulation are discussed. In air-breathing fish, the gut may gain particular importance for the uptake of ions. In addition, tissues frequently exposed to environmental air encounter much higher oxygen partial pressures than typically observed in fish tissues. Physostomous fish using the swimbladder for aerial respiration, for example, will encounter aerial oxygen partial pressure at the swimbladder epithelium when frequently gulping air in hypoxic water. Hyperoxic conditions or rapid changes in oxygen partial pressures result in an increase in the production of reactive oxygen species (ROS). Accordingly, in air-breathing fish, strategies of ionoregulation may be greatly modified, and the ROS defense capacity of air-exposed tissues is improved.     

The regulation of regulation: interleukin‐10 increases CD4+ CD25+ regulatory T cells but impairs their immunosuppressive activity in murine models with schistosomiasis japonica or asthma

CD4⁺ CD25⁺ Foxp3⁺ regulatory T (Treg) cells play an important role in maintaining immune homeostasis. Interleukin‐10 (IL‐10), a cytokine with anti‐inflammatory capacities, also has a critical role in controlling immune responses. In addition, it is well known that production of IL‐10 is one of the suppression mechanisms of Treg cells. However, the action of IL‐10 on Treg cells themselves remains insufficiently understood. In this study, by using a Schistosoma japonicum‐infected murine model, we show that the elevated IL‐10 contributed to Treg cell induction but impaired their immunosuppressive function. Our investigations further suggest that this may relate to the up‐regulation of serum transforming growth factor (TGF‐β) level but the decrease in membrane‐bound TGF‐β of Treg cells by IL‐10 during S. japonicum infection. In addition, similar IL‐10‐mediated regulation on Treg cells was also confirmed in the murine model of asthma. In general, our findings identify a previously unrecognized opposing regulation of IL‐10 on Treg cells and provide a deep insight into the precise regulation in immune responses.     

Combined therapies to treat complex diseases: The role of the gut microbiota in multiple sclerosis

The commensal microbiota has emerged as an environmental risk factor for multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) models have shown that the commensal microbiota is an essential player in triggering autoimmune demyelination. Likewise, the commensal microbiota modulates the host immune system, alters the integrity and function of biological barriers and has a direct effect on several types of central nervous system (CNS)-resident cells. Moreover, a characteristic gut dysbiosis has been recognized as a consistent feature during the clinical course of MS, and the MS-related microbiota is gradually being elucidated. This review highlights animal studies in which commensal microbiota modulation was tested in EAE, as well as the mechanisms of action and influence of the commensal microbiota not only in the local milieu but also in the innate and adaptive immune system and the CNS. Regarding human research, this review focuses on studies that show how the commensal microbiota might act as a pathogenic environmental risk factor by directing immune responses towards characteristic pathogenic profiles of MS. We speculate how specific microbiome signatures could be obtained and used as potential pathogenic events and biomarkers for the clinical course of MS. Finally, we review recently published and ongoing clinical trials in MS patients regarding the immunomodulatory properties exerted by some microorganisms. Because MS is a complex disease with a large variety of associated environmental risk factors, we suggest that current treatments combined with strategies that modulate the commensal microbiota would constitute a broader immunotherapeutic approach and improve the clinical outcome for MS patients.     

Interleukin-10 Directly Inhibits CD8+ T Cell Function by Enhancing N-Glycan Branching to Decrease Antigen Sensitivity

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Evidence of Broad Deficits in Emotion Regulation Associated with Chronic Worry and Generalized Anxiety Disorder

This study examined the relationship between emotion regulation deficits and GAD-related outcomes in an analogue sample. Consistent with hypotheses, general emotion dysregulation was associated with reports of chronic worry and with analogue GAD status. Also, specific regulation deficits, including deficits in emotional clarity, acceptance of emotions, ability to engage in goal directed behaviors when distressed, impulse control, and access to effective regulation strategies, were associated with worry and analogue GAD above and beyond variance contributed by negative affectivity. These findings provide additional preliminary evidence for an emotion regulation deficit model of GAD and are discussed in terms of clinical implications and directions for future research.