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Publications

Journal Article Ppublish

PubMed: 42541333 DOI: 10.1096/fj.202504879R

NLRC5-Deficient Macrophages Promote a Tumor-Permissive Phenotype via AXL- and MERTK-Mediated Efferocytosis.

FASEB J 40(15):e72156

Authors: Shambel Araya Haile, Alessandra Gatta, Nina Colon, Dana J Philpott, Thomas A Kufer, Le Ying, Dongmei Tong, Richard L Ferrero

Affiliations

  • Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • Department of Molecular and Translational Science, Monash University, Melbourne, Victoria, Australia.
  • Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Veterinary Sciences, Università di Pisa, Pisa, Italy.
  • Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
  • Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.

Abstract

The innate immune protein NLRC5 plays a key role in cancer immune surveillance. Reduced NLRC5 expression is associated with a poor prognosis for many types of cancers. Previously, we showed that mice with a myeloid-specific deletion of Nlrc5 (Nlrc5 mø-KO) develop gastric lymphoid lesions to Helicobacter infection resembling early-stage marginal zone lymphoma. We hypothesized that NLRC5 deficiency may promote a tumor-permissive microenvironment mediated by tumor-associated macrophages (TAMs). Consistent with this hypothesis, splenic macrophages from Helicobacter-infected Nlrc5 mø-KO mice had upregulated expression of genes encoding the TAM receptor tyrosine kinases, Axl and Mertk. The levels of AXL and MERTK gene expression and MERTK phosphorylation were increased in NLRC5 -/- THP-1 macrophages when compared with WT cells. In response to Helicobacter stimulation, Nlrc5 -/- macrophages had significantly elevated anti-inflammatory responses (IL-10, TGF-β, Socs1, Socs3) compared with WT cells. Importantly, Nlrc5 -/-macrophages showed enhanced efferocytosis and reduced antigen presentation to CD8 + T cells. Pretreatment of macrophages with AXL and MERTK inhibitors (R428, UNC2025) resulted in reduced efferocytosis and phosphorylation of downstream signaling molecules, STAT3 and ERK1/2. We propose that defective NLRC5 signaling in macrophages leads to tumor-permissive responses, thereby promoting the development of gastric lymphoid neogenesis to Helicobacter infection.

MeSH

Cells, Genes, C-Mer Tyrosine Kinase, Macrophages, Neoplasms, Phenotype, Infections