Epithelial-Cell-Derived Phospholipase A 2 Group 1B Is an Endogenous Anthelmintic

Entwistle, Lewis J.; Pelly, Victoria S.; Coomes, Stephanie M.; Kannan, Yashaswini; Perez-Lloret, Jimena; Czieso, Stephanie; Santos, Mariana Silva dos; MacRae, James I.; Collinson, Lucy M.; Sesay, Abdul Karim; Nikolov, Nikolay P.; Metidji, Amina; Helmby, Helena; Hui, David Y.; Wilson, Mark S.

doi:10.1016/j.chom.2017.09.006

Cited by 42 publications

(41 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…34 Furthermore, the epithelial cell-derived phospholipase A2 group 1B degrades phospholipids in L3 of Hp and this enzyme is actually inhibited by IL-4R signaling in organoid cultures. 35 Taken together, we demonstrate that expression of a constitutively active version of STAT6 in IECs promotes proliferation and differentiation of secretory IECs and orchestrates protective immunity against helminths at two distinct anatomical locations: the submucosa and the lumen of the SI. This finding provides the basis for further investigations on STAT6-regulated genes in IECs that mediate these effects.…”

Section: Discussionmentioning

confidence: 57%

Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths

et al. 2019

View full text Add to dashboard Cite

Intestinal epithelial cells (IECs) constitute an important barrier between host and pathogen. Immune mechanisms that provide protection against gastrointestinal helminths often require IL-4Rα-induced activation of STAT6-regulated genes in IECs. However, it is not known whether STAT6 activation in IECs enhances protective immunity against helminths. Furthermore, the regulation of proliferation and differentiation processes of the intestinal epithelium by IEC-intrinsic STAT6 signaling remains unclear. To address these questions, we generated mice with specific expression of a constitutively active version of STAT6 in IECs. These VillinCre_STAT6vt mice show accumulation of secretory IECs, increased proliferation of IECs and lengthening of the small intestine. They rapidly expelled Nippostrongylus brasiliensis worms even in the absence of T cells. Furthermore, primary infection with Heligmosomoides polygyrus resulted in larval trapping in the submucosa and the fecundity of adult worms was severely impaired. Our results reveal an important IEC-intrinsic role of STAT6-regulated genes for intestinal homeostasis and protective immunity against helminths.Mucosal Immunology (2019) 12:413-424; https://doi.

show abstract

Section: Discussionmentioning

confidence: 57%

Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths

et al. 2019

View full text Add to dashboard Cite

show abstract

“…This may have evolved to protect the host from microbial exposure during helminth infection, or as a helminthdriven strategy for modulating host immune responses. 95 While some aspects of anti-helminth host immunity are dependent on the microbiota, 96 it is also possible that helminths have evolved the ability to expand those microbiota species that benefit their own survival. The hatching of T. muris eggs in the ceca of mice is dependent on the presence of microbiota, 97 and supplementation with Lactobacilli species renders mice more susceptible to both T. muris and H. polygyrus infection.…”

Section: Discussionmentioning

confidence: 99%

The impact of a helminth-modified microbiome on host immunity

2018

View full text Add to dashboard Cite

Intestinal helminths have well-characterized modulatory effects on mammalian immune pathways. Ongoing helminth infection has been associated with both the suppression of allergies and an altered susceptibility to microbial infections. Enteric helminths share a niche with the intestinal microbiota, and the presence of helminths alters the microbiota composition and the metabolic signature of the host. Recent studies have demonstrated that the helminth-modified intestinal microbiome has the capacity to modify host immune responses even in the absence of live helminth infection. This article discusses the mechanisms by which helminths modify the intestinal microbiome of mammals, and reviews the evidence for a helminth-modified microbiome directly influencing host immunity during infectious and inflammatory diseases. Understanding the multifaceted mechanisms that underpin helminth immunomodulation will pave the way for novel therapies to combat infectious and inflammatory diseases.

show abstract

“…Members of the chymotrypsin and elastase family are enzymes involved in the degradation of the outer membrane protein OmpA of Gram-negative bacteria (39). Although phospholipase A2 (group IB; pla2g1b) mainly acts as a lipid degrading enzyme, phospholipase A2 (PLA2) produced from intestinal epithelial cells is also important for defense against parasite infection (40). Furthermore, phospholipase A2 (group IIA; pla2g2A), which is classified as the same phospholipase, is known as a marker of Paneth cells.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-17A/F1 Deficiency Reduces Antimicrobial Gene Expression and Contributes to Microbiome Alterations in Intestines of Japanese medaka (Oryzias latipes)

et al. 2020

View full text Add to dashboard Cite

In mammals, interleukin (IL)-17A and F are hallmark inflammatory cytokines that play key roles in protection against infection and intestinal mucosal immunity. In the gastrointestinal tract (GI), the induction of antimicrobial peptide (AMP) production via Paneth cells is a fundamental role of IL-17A and F in maintaining homeostasis of the GI microbiome and health. Although mammalian IL-17A and F homologs (referred to as IL-17A/F1-3) have been identified in several fish species, their function in the intestine is poorly understood. Additionally, the fish intestine lacks Paneth cells, and its GI structure is very different from that of mammals. Therefore, the GI microbiome modulatory mechanism via IL-17A/F genes has not been fully elucidated. In this study, Japanese medaka (Oryzias latipes) were used as a teleost model, and IL-17A/F1-knockout (IL-17A/F1-KO) medaka were established using the CRISPR/Cas9 genome editing technique. Furthermore, two IL-17A/F1-deficient medaka strains were generated, including one strain containing a 7-bp deletion (-7) and another with an 11-bp addition (+11). After establishing F2 homozygous KO medaka, transcriptome analysis (RNA-seq) was conducted to elucidate IL-17A/F1-dependent gene induction in the intestine. Results of RNA-seq and real-time PCR (qPCR) demonstrated down-regulation of immune-related genes, including interleukin-1β (IL-1β), complement 1q subunit C (C1qc), transferrin a (Tfa), and G-type lysozyme (LyzG), in IL-17A/F1-KO medaka. Interestingly, protein and lipid digestive enzyme genes, including phospholipase A2, group IB (pla2g1b), and elastase-1-like (CELA1), were also downregulated in the intestines of IL-17A/F1-KO medaka. Furthermore, to reveal the influence of these downregulated genes on the gut microbiome in IL-17A/F1-KO, 16S rRNA-based metagenomic sequencing analysis was conducted to analyze the microbiome constitution. Under a non-exposed state, the Okamura et al. Role of IL-17A/F1 in Teleost Intestineintestinal microbiome of IL-17A/F1-KO medaka differed at the phylum level from wild-type, with significantly higher levels of Verrucomicrobia and Planctomycetes. Additionally, at the operational taxonomic unit (OTU) level of the human and fish pathogens, the Enterobacteriaceae Plesiomonas shigelloides was the dominant species in IL-17A/F1-KO medaka. These findings suggest that IL-17A/F1 is involved in the maintenance of a healthy gut microbiome.

show abstract

Epithelial-Cell-Derived Phospholipase A 2 Group 1B Is an Endogenous Anthelmintic

Cited by 42 publications

References 47 publications

Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths

Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths

The impact of a helminth-modified microbiome on host immunity

Interleukin-17A/F1 Deficiency Reduces Antimicrobial Gene Expression and Contributes to Microbiome Alterations in Intestines of Japanese medaka (Oryzias latipes)

Contact Info

Product

Resources

About