Macrophages modulate bacterial persistence and gastric pathology during Helicobacter pylori infection (INC4P.346)

Abstract

Abstract Based on preliminary data suggesting that macrophages are critical regulators of Helicobacter pylori colonization and gastric pathology, we investigated how macrophage phenotypes shape the outcome of infection and persistence. The loss of PPARγ in the myeloid compartment favors a 5 to 10-fold decrease in bacterial loads at the expense of more severe gastric lesions. PPARγ-deficient macrophages present altered control of transcription factors such as NFκB, which results in a pro-inflammatory phenotype. Stomach lamina propria analyses at weeks 0 to 4 post-infection revealed increased levels of CD11b+ F4/80hi CD64+ CR3CR1+ macrophages in WT mice, while PPARγKO mice failed to expand and maintain such population. Macrophage depletion using clodronate liposomes resulted in a significant reduction of gastric H. pylori in WT mice, thus abrogating the differences in bacterial loads observed between WT and PPARγKO mice. In vitro co-culture of H. pylori with bone marrow derived macrophages showed that either PPARγ loss or pharmacological blockade enhances bactericidal activity, which is associated to significant differential expression of chil1, etv5, iigp1, ptger4, sqle, osm, hspa2 and rptoros levels as revealed by global transcriptome analyses. Hence, macrophages facilitate H. pylori infection by 1) serving as bacterial reservoirs and allowing intracellular replication, and 2) favoring a gastric regulatory response that favors persistence.