Chronic Helicobacter pylori infection is associated with more than 90% cases of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, a form of B-cell lymphoma. We have generated a mouse model in which animals lacking the innate immune molecule Nlrc5 in myeloid cells (Nlrc5m⌀-KO) develop gastric MALT, a precursor to this lymphoma, in response to chronic Helicobacter infection. RNA-seq analyses showed that splenic macrophages from these mice have a gene expression profile similar to that of tumour-associated macrophages (TAMs) with immunosuppressive and pro-tumorigenic functions. The identified genes included Mertk and Axl, which are expressed by TAMs and involved in limiting inflammation by promoting efferocytosis i.e. phagocytosis of dead cells. We hypothesized that defective NLRC5 signalling in macrophages leads to tumour-permissive responses that promote the development of gastric B-cell MALT lymphoma to Helicobacter infection. To investigate this, we assessed efferocytosis, bacterial phagocytosis and cytokine gene expression in wild-type (WT) and Nlrc5-/- or NLRC5-/- macrophages. Consistent with the RNA-seq data, we showed that AXL expression is upregulated in NLRC5-/- THP-1-derived macrophages in response to Helicobacter (P<0.01, Two-way ANOVA) compared to WT cells. Furthermore, Nlrc5-/- and NLRC5-/- macrophages exhibited increased efferocytosis (14% and 17%, respectively; P<0.05, Mann-Whitney U test) and bacterial phagocytosis (1.5- and 1.7-fold, respectively; P<0.01, Two-way ANOVA), relative to WT counterparts. Nlrc5-/- splenic macrophages also demonstrated significantly elevated expression levels of anti-inflammatory cytokines (Il10, Tgfb) and suppressors of cytokine signalling (Socs1, Socs3), in response to stimulation with Helicobacter bacteria or LPS, compared to WT cells (P<0.05, two-way ANOVA). These findings suggest that defective NLRC5 signalling in macrophages leads to tumour-permissive responses promoting the development of gastric B-cell MALT lymphoma to Helicobacter infection.