Role of Macrophages in the Altered Epithelial Function during a Type 2 Immune Response Induced by Enteric Nematode Infection

Notari, Luigi; Riera, Diana C.; Sun, Rex; Bohl, Jennifer A.; McLean, Leon; Madden, Kathleen B.; Rooijen, Nico van; Vanuytsel, Tim; Urban, Joseph F.; Zhao, Aiping; Shea‐Donohue, Terez

doi:10.1371/journal.pone.0084763

Cited by 34 publications

(38 citation statements)

References 66 publications

(81 reference statements)

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“…The details of the mechanism is still unclear, but Notari et al . presented a model for changes in epithelial glucose handling in response to Nippostrongylus brasiliensis (Nb) infection in BALB/c mice [34]. This mouse strain is not a diabetic model, but the authors pointed out that the downregulation of SGLT1 after Nb infection is dependent on AAMacs (M2) but not on GLUT2.…”

Section: Discussionmentioning

confidence: 99%

“…RNA levels were measured on a NanoDrop spectrophotometer (Thermo Scientific, Wilmington, DE, U.S.A.), and cDNA was synthesized with random primers and SuperScript II (Life Technologies, Inc.). Primer sequences for IL-4, IL-13 [30], IL-10 [10], Arginase 1 (ARG1), FIZZ1, YM1 [54], fatty acid synthase (FAS) [52] and GLUT2 [34] have been described previously. Real-time PCR was performed using Brilliant SYBR Green QPCR Master Mix III (Stratagene, La Jolla, CA, U.S.A.) with an MX3000P system (Stratagene).…”

Section: Methodsmentioning

confidence: 99%

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Regulation of type 2 diabetes by helminth-induced Th2 immune response

Morimoto

Azuma

Kadowaki

et al. 2016

The Journal of Veterinary Medical Science

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Helminth-induced type 2 cytokines increase the number of regulatory T cells and alternatively activated macrophages, resulting in modulation of the host–immune system. Studies on these parasite-induced immunoregulatory mechanisms might contribute to the development of new therapies for inflammatory diseases, including type 2 diabetes (T2D). Previous studies have suggested that progression of obesity-associated metabolic abnormalities is under pathophysiological control of CD4+ T cells. Glucose absorption through the intestinal epithelium reduced after infection in a STAT-6-dependent manner. In this study, we investigated whether infection with the gastrointestinal nematode parasite Heligmosomoides polygyrus (Hp) can modulate T2D-associated pathology in a mouse model (KK-Ay/TaJcl). KK-Ay/TaJcl mice were inoculated with infective third-stage Hp larvae and studied at Day 8 following infection. Uninfected KK-Ay/TaJcl mice showed high blood glucose levels even 120 min after administration of glucose by IP injection. However, it was significantly improved in the infected group. HOMA-IR, fat accumulation and FAS gene expression in the liver were significantly decreased by Hp infection. GLUT2 gene expression in this group was significantly lower than that in the uninfected diabetic mice, which might be related to the decrease in glucose absorption in the parasite-infected intestine. In conclusion, helminth-induced type 2 immune responses might contribute to T2D disease control.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Regulation of type 2 diabetes by helminth-induced Th2 immune response

Morimoto

Azuma

Kadowaki

et al. 2016

The Journal of Veterinary Medical Science

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“…Among those first responders, macrophages accumulate in the mucosa as well as in the smooth muscle of the intestine. More importantly, the type 2 cytokines IL-4 and IL-13 induce alternative activation of macrophages into the M2 phenotype that is indispensable to the morphological and functional alterations of intestinal smooth muscle and epithelial cells (22,39). The absence of IL-25 resulted in a delayed type 2 immune response leading to defective M2 development.…”

Section: Discussionmentioning

confidence: 99%

Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri

et al. 2016

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f Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb, were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri. Genetic deletion of IL-25 (IL-25 ؊/؊ ) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25 ؊/؊ mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25 ؊/؊ mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.A lthough studies using mouse models have advanced our understanding of the molecular and cellular mechanisms underlying host protection against nematode infection, many of the details remain to be fully elucidated. Infection with gastrointestinal nematode parasites induces a polarized Th2 immune response featuring elevated levels of production of interleukin-4 (IL-4), IL-5, and IL-13. IL-4 and IL-13 activate STAT6 signaling pathways, leading to characteristic alterations in intestinal function that facilitate worm expulsion. IL-25, also called IL-17E, is a cytokine member of the IL-17 family that includes IL-17A through IL-17F. Unlike other members of the IL-17 family that are involved in various inflammatory pathologies, IL-25 possesses immune-modulating properties that inhibit Th1/Th17-associated inflammation.It has been observed that intestinal epithelium-derived IL-25 plays a pivotal role in the initiation of the host protective immune cascade against nematode infection. In particular, intestinal epithelial tuft cells produce IL-25 (1, 2) in response to early-stage worm infection, leading to the expansion and activation of type 2 innate lymphoid cells (ILC2), a recently identified noncytotoxic innate lymphoid cell (ILC) family member that has a classic lymphoid cell morphology but that lacks the expression of cell surface markers of other known immune lymphocytes (3, 4). The activated ILC2 then release Th2-associated cytokines IL-5 a...

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“…One possibility is that they simply do not survive long enough to be able to progress through the entire waterfall, which normally takes up to a week to complete. 107 186,187 and by producing chemokines that recruit additional anti-parasite effector cells such as eosinophils. 168,177 In contrast to what has been described in the pleural or peritoneal cavities, cell niche via stimulation of PGE2 production from stromal cells.…”

Section: Macrophages In Intestinal Inflammationmentioning

confidence: 99%