CD14-deficient macrophages show compromised tolerance induction after repeated antigen stimulation and trigger intestinal inflammation in an acute mouse colitis model
BUCHHEISTER S. 1, ROSIER A. 1, LIENENKLAUS S. 1, BLEICH A. 1
1 Hannover Medical School; Institute for Laboratory Animal Science and Central Animal Facility, Hannover, Germany
Disturbance of the gastrointestinal homeostasis plays a key role in inflammatory bowel disease (IBD) development. Although the exact pathomechanisms remain unknown, there is profound evidence that intestinal inflammation is mainly driven by overactivated macrophages. We previously identified the “cluster of differentiation 14” (CD14) protein as a protective factor in experimental IBD (BUCHHEISTER, 2017). CD14 is a well-established pattern-recognition-receptor, involved in inflammatory and anti-inflammatory processes in a cell-type dependent manner. Since it was shown that CD14 ameliorates chronic inflammation through induction of tolerance mechanisms (SAHAY 2009), CD14-dependent anti-inflammatory signaling in intestinal macrophages might be an interesting target for IBD treatment. Therefore, we aimed to analyze the CD14-dependent effects of intestinal macrophages after repeated antigen stimulation and during acute intestinal inflammation in the Dextran- Sulfate-Sodium- (DSS) model.
Macrophages were isolated from wildtype (wt) and Cd14-deficient (Cd14-/-) mice and analyzed for cytokine expression patterns after repeated Lipopolysaccharide (LPS) stimulations. Furthermore, intestinal inflammation was induced by DSS and disease phenotypes were compared between wt and Cd14-/- mice after depletion of intestinal macrophages by intraperitoneal injections of Clodronate-Liposomes.
Proinflammatory cytokine expression was strongly induced after exposure to LPS independent of CD14. Re-exposure to LPS hardly induced proinflammatory cytokine levels in wt-controls, whereas Cd14-/--macrophages showed strikingly increased TNFα expression. On the contrary, IFN-β induction was strictly CD14-dependent, after both stimulations.
As expected, Cd14-/- mice developed more severe intestinal inflammation after DSS treatment compared to wt-controls. Remarkably, macrophage depletion by Clodronate-Liposomes reduced the severity of disease development in both genotypes and prevented the detrimental effects of Cd14--deficiency during intestinal inflammation.
These findings clearly demonstrate, that Cd14-deficiency compromises tolerance induction after repeated antigen stimulation and triggers intestinal inflammation in the acute DSS colitis model likely through overactivated macrophages. Therefore, CD14-dependent anti-inflammatory signaling in intestinal macrophages might be an interesting therapeutic target for IBD treatment.