The protection role of Atg16l1 in CD11c + dendritic cells in murine colitis

Abstract

The autophagy-related 16-like 1 gene (Atg16l1) is associated with inflammatory bowel disease (IBD) and has been shown to play an essential role in paneth cell function and intestinal homeostasis. However, the functional consequences of Atg16l1 deficiency in myeloid cells, particularly in dendritic cells (DCs), are not fully characterized. The aim of this study is to investigate the functional consequence of Atg16l1 in CD11c+ DCs in murine colitis. We generated mice deficient in Atg16l1 in CD11c+ DCs. Dextran Sulfate Sodium (DSS) and S. typhimurium infection induced colitis was used to assess the role of DCs specific Atg16l1 deficiency in vivo in murine colitis. Bone marrow derived dendritic cells (BMDC) were isolated and autophagy function was assessed with microtubule-associated protein 1 light chain 3β (Map1lc3b or LC3) by western blot. Uptake of Salmonella enteric serovar typhimurium (S. typhimurium) was assessed by flow cytometry and transmission electron microscopy (TEM). The production of reactive oxygen species (ROS) and intracellular S. typhimurium killing in BMDCs were assessed. We showed worsened colonic inflammation in Atg16l1 deficiency mice in DSS induced murine colitis with increased proinflammatory cytokines of IL-1β and TNF-α. Mechanistic studies performed in primary murine BMDCs showed that Atg16l1 deficiency increased ROS production, reduced microbial killing and impaired antigen processing for altered intracellular trafficking. Together, these results indicate impaired CD11c+ DCs function with Atg16l1 deficiency contributes to the severity of murine colitis.

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD

“…Murine macrophages expressing dysfunctional ATG16L1 produce higher amount of ROS following lipopolysaccharide (LPS) stimulation compared to WT macrophages [51]. Consistently, ROS production by Atg16l1-deficient murine DCs is increased compared to WT DCs either at baseline or upon Salmonella Typhimurium infection, and this is associated with an increased number of mitochondria probably due to impaired mitophagy [52]. In regulating ROS level, autophagy has an impact on cytokine secretion [53].…”

Ancient Nuclear Receptor VDR With New Functions: Microbiome and Inflammation

“…47,48 These mice exhibit increased susceptibility to DSS-induced colitis due to impaired autophagy. Both macrophages and dendritic cells deficient in ATG16L1 have impaired processing of MHC class II antigens and thus impaired CD4+ T cell activation.…”

“…Both macrophages and dendritic cells deficient in ATG16L1 have impaired processing of MHC class II antigens and thus impaired CD4+ T cell activation. 47,48 ATG16L1 is also critical for T cell function. Targeted deletion of ATG16L1 in CD4+ T cells results in increased Th2 expansion and impaired Treg development leading to spontaneous intestinal inflammation.…”

Autophagy: A Potential Therapeutic Target for Reversing Sepsis-Induced Immunosuppression

“…The autophagy does function as an immunomodulatory mechanism for DCs, as it exhibits disturbed antigen processing and presentation and fails to prime T cells with deficient of autophagy-associated genes, such as Atg16, Atg7, and Beclin-1 ( 37 , 83 , 84 ). Autophagy activation has been proved to enhance antigen presentation of DCs by increasing expression of MHC II molecules, suggesting that autophagy induction possesses a critical role in maintaining DC function ( 85 ).…”

“…In addition, the effects of autophagy-associated genes varied with different types, Beclin-1, for example, Beclin-1 +/‒ DCs revealed suppressed expression of MHC II molecules and pro-inflammatory cytokines and further induced Th2 polarization in comparison with wild controls, indicating a protective role of Beclin-1 in maintaining homeostasis of immune response ( 84 ). Likewise, DCs with autophagy-related 16-like 1 (Atg16L1) gene deficiency showed excessive production of reactive oxygen species and abnormal antigen processing under colitis exposure ( 83 ). Yet interestingly, Atg16L1 was found to avoid lethal T cell alloreactivity by inhibiting the immune response of DCs in graft-versus-host disease, suggesting that the protective role of autophagy in DCs varied with disease types ( 86 ).…”