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Examining the Role of Nasopharyngeal-associated Lymphoreticular Tissue NALT in Mouse Responses to Vaccines
Published on: August 1, 2012
Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue
Michelle Chonwerawong1, Jonathan Ferrand2, Hassan Mohammad Chaudhry2
1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Victoria, Australia.
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.
Insights
Nucleotide-binding oligomerization domain-like receptors family CARD domain-containing 5 (NLRC5) negatively regulates gastric inflammation and lymphoid formation during Helicobacter infection. Dysregulated NLRC5 signaling in macrophages may drive B-cell lymphomagenesis in chronic infections.
Area of Science:
- Immunology
- Gastroenterology
- Infectious Diseases
Background:
- Helicobacter pylori infection triggers host inflammatory responses.
- Uncontrolled inflammation can cause host tissue damage.
- The role of NLRC5 in Helicobacter-induced immune responses requires elucidation.
Purpose of the Study:
- To investigate the immune-regulatory function of NLRC5 in Helicobacter infection.
- To determine NLRC5's role in gastric inflammation and lymphoid tissue formation.
- To assess NLRC5's impact on B-cell lymphomagenesis.
Main Methods:
- Analysis of gastric biopsies from H. pylori-infected patients.
- Studies using myeloid-specific NLRC5 knockout (Nlrc5møKO) and control mice infected with H. felis.
- In vitro studies with human THP-1 macrophages (NLRC5-deficient and control) stimulated with Helicobacter.
Main Results:
- NLRC5 mRNA levels were elevated in human gastric tissues with H. pylori infection and correlated with gastritis severity.
- NLRC5 deficiency in macrophages enhanced chemokine and cytokine production in response to H. pylori.
- Nlrc5møKO mice exhibited gastric hyperplasia, splenomegaly, increased antibodies, and MALT lymphoma-like B-cell follicles, driven by B-cell-activating factor.
Conclusions:
- NLRC5 acts as a negative regulator of gastric inflammation and mucosal lymphoid formation during Helicobacter infection.
- Aberrant NLRC5 signaling in macrophages contributes to B-cell lymphomagenesis in chronic Helicobacter infections.
