Projects per year
Abstract
Background & Aims: Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, nucleotide-binding oligomerization domain-like receptors (NLR) family CARD domain-containing 5 (NLRC5), in patients and mice with Helicobacter infection. Methods: We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5møKO) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative polymerase chain reaction. THP-1 cells (human macrophages, controls) and NLRC5–/– THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed. Results: Levels of NLRC5 messenger RNA were significantly increased in gastric tissues from patients with H pylori infection, compared with patients without infection (P <.01), and correlated with gastritis severity (P <.05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5−/− THP-1 macrophages than by control THP-1 cells (P <.05). After 3 months of infection with H felis, Nlrc5mø-KO mice developed gastric hyperplasia (P <.0001), splenomegaly (P <.0001), and increased serum antibody titers (P <.01), whereas control mice did not. Nlrc5mø-KO mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P <.0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell–activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5mø-KO mice. Conclusions: NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection.
Original language | English |
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Pages (from-to) | 169-182 |
Number of pages | 22 |
Journal | Gastroenterology |
Volume | 159 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jul 2020 |
Keywords
- B-lymphocytes
- BAFF
- Gastric Carcinogenesis
- MALT lymphoma
Projects
- 3 Finished
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NLRC5, a new regulator of Helicobacter-induced inflammation
Ferrero, R.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/16 → 31/12/19
Project: Research
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Epithelial cell signalling and host response to virulent helicobacter pylori strains
Ferrero, R. & Jenkins, B.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/11 → 31/12/13
Project: Research
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NHMRC Research Fellowship
Ferrero, R.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/10 → 31/12/19
Project: Research
Equipment
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Genome Modification Platform
Jeanette Rientjes (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility
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Histology Platform
Camilla Cohen (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility