Calcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis

Mencarelli, Andrea; Khameneh, Hanif Javanmard; Frič, Jan; Vacca, Maurizio; Daker, Sary El; Janela, Baptiste; Tang, Jing; Nabti, Sabrina; Balachander, Akhila; Lim, Tong Seng; Ginhoux, Florent; Ricciardi‐Castagnoli, Paola; Mortellaro, Alessandra

doi:10.1038/s41467-018-03495-3

Cited by 27 publications

(25 citation statements)

References 32 publications

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“…The impact on small intestinal mucosa is particularly profound, altering the morphology, structure and function of the intestinal epithelia. Weaning induces both acute and long-lasting structural and functional changes in the small intestine including shortening of the villi (villous atrophy) and an increase in crypt depth 3,16 . For piglets, the small intestine is the main organ for nutrient absorption and transportation, and a healthy small intestinal mucosa is important for ensuring a normal digestion function as nutrient absorption relies heavily on the villi of small intestine.…”

Section: Discussionmentioning

confidence: 99%

Duan-Nai-An, A Yeast Probiotic, Improves Intestinal Mucosa Integrity and Immune Function in Weaned Piglets

Zhaxi

Meng

Wang

et al. 2020

Sci Rep

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Post-weaning diarrhea commonly occurs in piglets and results in significant economic loss to swine producers. non-antibiotic measures for managing post-weaning diarrhea are critically needed. Duannai-An, a probiotic produced from the yeast fermentation of egg whites, was previously shown to optimize intestinal flora and reduce the incidence of clinical diarrhea in weaning piglets. To study the effects of Duan-Nai-An on mucosal integrity and immunity in pig intestine, we examined the microstructure and ultrastructure of the intestines of weaned pigs with or without Duan-nai-An as a feed supplement. the piglets of the Duan-nai-An-fed group developed intestines with intact columnar epithelia covered by tightly packed microvilli on the apical surface. However, piglets of the control group (no supplement) showed villous atrophy and thinning, microvillus slough, and in the severe cases, damage of intestinal epithelia and exposure of the underlying lamina propria. Moreover, piglets of the Duan-nai-An-fed group showed apparent plasmocyte hyperplasia, increased lymphoid nodule numbers, well-developed peyer's patchs, and apparent germinal centers. the lymphoid tissues of the control group were far less developed, showing lymph node atrophy, lymphocyte reduction, degeneration, and necrosis. these results indicate that Duan-nai-An improves the development of the intestinal structures and lymphoid tissues and promotes intestinal health in weaned piglets. The gastrointestinal (GI) tract is the largest immune organ in the body 1,2. The epithelial lining of the GI tract is the surface that is in close contact with the external environment. The GI tract also provides the microenvironment for the development and differentiation of the intestinal immune cells. The intestinal epithelial cells play important roles not only in food digestion and nutrient absorption, but also in immune defense and immune tolerance 3. More than 50% of the body's lymphoid tissue is distributed in the intestinal mucosa, bearing an important immune function and constituting the body's first barrier against pathogenic microorganism invasions 4. A diverse and large number of microorganisms are found in the GI tract. Gut microbiota play very important roles in the growth, anti-infection, immune regulation, metabolism and intestinal health of the host 5-8 , and most studies mainly focused on evaluating the impact of bacterial flora on animal nutrition 9-11. Recently, more and more work has been devoted to understanding the microbiota-intestinal mucosa interaction, how the interaction form a mechanical, immunological, and biological barrier against pathogen invasion and endotoxin translocation, and how gut microbiota modulates the development and function of the mucosal immune system 5,12-15. Weaning is one of the most stressful events in the swine production process and disturbs the intestinal flora of piglets, often compromising the intestinal structure and mucosal barrier 16. Because of the disruption, weaning piglets may have decreased intestinal mucosal im...

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Section: Discussionmentioning

confidence: 99%

Duan-Nai-An, A Yeast Probiotic, Improves Intestinal Mucosa Integrity and Immune Function in Weaned Piglets

Zhaxi

Meng

Wang

et al. 2020

Sci Rep

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“…As a major substrate of calcineurin, nuclear factor of activated T cells (NFAT) is widely distributed in various tissues and cell types (3). Activated calcineurin directly dephosphorylates NFATs in the cytoplasm and induces their translocation to the nucleus (4)(5)(6). In addition to dephosphorylating NFATs, calcineurin is recruited to the T cell receptor (TCR) signaling complex, where it reverses the inhibitory phosphorylation of lymphocyte-specific protein tyrosine kinase (LCK) on serine 59 (7,8).…”

Section: Introductionmentioning

confidence: 99%

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance

Zhang¹,

Liu²,

Cao³

et al. 2019

Journal of Clinical Investigation

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“…A successful strategy for drug delivery in patients with UC has been through a prodrug approach used in relation to 5-aminosalicilic acid (5-ASA) [17,18]. In this model, the prodrugs of 5-ASA bound to an additional moiety through an azo-bond, where bacterial azoreductases located in the colon activate the 5-ASA prodrug and selectively liberate free 5-ASA in the colon [19,20]. Some of these approaches are associated with inconsistent efficacy and interpatient variability [21].…”

Section: Introductionmentioning

confidence: 99%

Colon-Targeted Therapy of Tacrolimus (FK506) in the Treatment of Experimentally Induced Colitis

et al. 2020

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Background/Aims: Inflammatory bowel disease is a chronic or remitting/relapsing intestinal inflammation, which comprises Crohn’s disease and ulcerative colitis (UC). Severe UC is a life-threatening condition that requires corticosteroids (CS) as a first-line rescue therapy. Some patients are refractory to CS and may require alternative immunosuppressive therapy. Oral tacrolimus (FK506), an immunosuppressive agent, has been reported to be effective in the management of severe refractory UC, but it can cause serious adverse effects. This work aims to study the effect of tacrolimus delivered by a colon-targeted delivery system (CTDS) in a dextran sulfate sodium (DSS)-induced animal model of colitis. Materials and Methods: We developed and evaluated an oral CTDS of tacrolimus (FK506) loaded pH-dependent polymeric microspheres, composed of Eudragit® S100 as a pH-sensitive polymer using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these microparticles in gastrointestinal tract (GIT) conditions were examined. A DSS-induced colitis rat model was used to evaluate the potential remedial and in vivo distribution of microspheres. Results: The pH-microspheres prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the rat GIT demonstrated that pH-microspheres were successfully delivered to the inflamed colon. Moreover, it also demonstrated a significant decrease of disease activity and expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1β (IL-1β), and IL-6, and minimized the histological and morphometric changes. Conclusion: The results confirmed the efficacy of tacrolimus (FK506) CTDs in the management of DSS-induced colitis.

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Calcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis

Cited by 27 publications

References 32 publications

Duan-Nai-An, A Yeast Probiotic, Improves Intestinal Mucosa Integrity and Immune Function in Weaned Piglets

Duan-Nai-An, A Yeast Probiotic, Improves Intestinal Mucosa Integrity and Immune Function in Weaned Piglets

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance

Colon-Targeted Therapy of Tacrolimus (FK506) in the Treatment of Experimentally Induced Colitis

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