Constitutive CD40 Signaling in Dendritic Cells Limits Atherosclerosis by Provoking Inflammatory Bowel Disease and Ensuing Cholesterol Malabsorption

Abstract

The costimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types, including mature dendritic cells (DCs), and is required for optimal T-cell activation and expansion. It remains undetermined whether and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here, the effects of constitutively active CD40 in DCs on atherosclerosis were examined using low-density lipoprotein-deficient (Ldlr) bone marrow chimeras that express a transgene containing an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the DC-specific CD11c promoter (DC-LMP1/CD40). As expected, DC-LMP1/CD40/Ldlr chimeras (DC-LMP1/CD40) showed increased antigen-presenting capacity of DCs and increased T-cell numbers. However, the mice developed extensive neutrophilia compared to CD40wt/Ldlr (CD40wt) chimeras. Despite overt T-cell expansion and neutrophilia, a reduction in conventional DC frequency and a dramatic (approximately 80%) reduction in atherosclerosis was observed. Further analyses revealed that cholesterol and triglyceride levels had decreased by 37% and 60%, respectively, in DC-LMP1/CD40 chimeras. Moreover, DC-LMP1/CD40 chimeras developed inflammatory bowel disease characterized by massive transmural influx of leukocytes and lymphocytes, resulting in villous degeneration and lipid malabsorption. Constitutive activation of CD40 in DCs results in inflammation of the gastrointestinal tract, thereby impairing lipid uptake, which consequently results in attenuated atherosclerosis.

Deletion of Ppard in CD11c + cells attenuates atherosclerosis in ApoE knockout mice

“…Previous studies showed that DCs regulate cholesterol metabolism by affecting lipid absorption in the small instestine, 35 or modulating lipid uptake in hepatic DCs through CD36 and further regulating hepatic triglyceride storage. 36 In our hands, although PPARδ is known to regulate fatty acid metabolism in many types of cells, we found that cholesterol and triglyceride levels were similar between Ppard DC-WT but not Ppard DC-KO mice.…”

Co-stimulators CD40-CD40L, a potential immune-therapy target for atherosclerosis: A review

“…Signaling and transcription factors (TRAM, MAPK, STAT5, NF-κB) Secreting cytokines (IL-12, MMPs, MIP-1, MCP-1, IL-8, TNF-α, IFN-γ) [44,60] Adipocytes, endothelial cells Promotion and formation of a stable plaque phenotype Leukocyte adhesion, inflammatory cell migration [51,52] Dendritic cells Attenuated atherosclerosis Lipid uptaking [7,56] Antigen-presenting cells CD40-TRAF2/3/5 interaction Inhibiting interaction between CD40 and TRAF6 [61,62] Endothelial cells Determining the atherosclerotic susceptibility sites Cytokines (ICAM-1, MCP-1, IL-6, IL-8, MMPs) the near future, there will be alternative approaches that are based on CD40-CD40L. As a result, the prospects for cellor signal-specific treatment of the CD40-CD40L interaction in atherosclerosis are promising and will require long-term investigation.…”

Helicobacter hepaticus is required for immune targeting of bacterial heat shock protein 60 and fatal colitis in mice

“…DC-LMP1/CD40 mice have been described previously. [24][25][26] They were generated by breeding CD11c-Cre mice 34 to LMP1/CD40 flStop mice, 35 which express a loxP-flanked stop-codonprotected LMP1/CD40 chimeric molecule. This caused constitutive CD40-signaling in CD11c + DCs and as a consequence, the DC-iTreg axis was altered and mice developed fatal colitis.…”

“…24 Loss of tolerogenic CD103 + DCs caused a lack of RORγt + Helios − iTregs and an increase of inflammatory IL-17 + IFN-γ + Th17/Th1 and IFN-γ + Th1 cells in the colon, resulting in the breakdown of mucosal tolerance and fatal colitis. [24][25][26] Of note, this model mimics the human IBD situation, as CD40-CD40L interactions are of relevance to the pathogenesis of IBD. [27][28][29][30][31][32][33] In the present study, we focused on microbialhost interactions in the CD40-mediated colitis model to determine how the intestinal microbiota modulates the host immune response.…”