Gut Commensal-Induced IκBζ Expression in Dendritic Cells Influences the Th17 Response

Abstract

Intestinal commensal bacteria can have a large impact on the state of health and disease of the host. Regulation of Th17 cell development by gut commensals is known to contribute to their dichotomous role in promoting gut homeostasis and host defense, or development of autoimmune diseases. Yet, the underlying mechanisms remain to be fully elucidated. One candidate factor contributing to Th17 differentiation, and the expression of which could be influenced by commensals is the atypical nuclear IκB protein IκBζ. IκBζ acts as a transcriptional regulator of the expression of Th17-related secondary response genes in many cell types including dendritic cells (DCs). Insights into the regulation of IκBζ in DCs could shed light on how these immune sentinel cells at the interface between commensals, innate and adaptive immune system drive an immune-tolerogenic or inflammatory Th17 cell response. In this study, the influence of two gut commensals of low (Bacteroides vulgatus) or high (Escherichia coli) immunogenicity on IκBζ expression in DCs and its downstream effects was analyzed. We observed that the amount of IκBζ expression and secretion of Th17-inducing cytokines correlated with the immunogenicity of these commensals. However, under immune-balanced conditions, E. coli also strongly induced an IκBζ-dependent secretion of anti-inflammatory IL-10, facilitating a counter-regulative Treg response as assessed in in vitro CD4+ T cell polarization assays. Yet, in an in vivo mouse model of T cell-induced colitis, prone to inflammatory and autoimmune conditions, administration of E. coli promoted an expansion of rather pro-inflammatory T helper cell subsets whereas administration of B. vulgatus resulted in the induction of protective T helper cell subsets. These findings might contribute to the development of new therapeutic strategies for the treatment of autoimmune diseases using commensals or commensal-derived components.

Emerging role of IκBζ in inflammation: Emphasis on psoriasis

“…Of interest, secretion of IL‐6 and IL‐10 in response to infection was found to be dependent on IκBζ in BMDCs. This study also showed that the commensals stimulate TLR4 signalling which in response stimulates the secretion of Th‐17‐inducing cytokines in BMDCs 93 . Moreover, IκBζ also upregulates Nlrp3 gene in bone marrow‐derived macrophages, thereby, playing crucial role in the activation of NLRP3 inflammasome 94 .…”

“…This study also showed that the commensals stimulate TLR4 signalling which in response stimulates the secretion of Th‐17‐inducing cytokines in BMDCs. 93 Moreover, IκBζ also upregulates Nlrp3 gene in bone marrow‐derived macrophages, thereby, playing crucial role in the activation of NLRP3 inflammasome. 94 Interestingly, the potential regulatory role of Nfkbiz in the skin immunity was exposed when Nfkbiz ‐deficient mice was found to spontaneously develop dermatitis along with expansion of Staphylococcus xylosus in the skin.…”

Atomic-Level Dissection of DC-SIGN Recognition of Bacteroides vulgatus LPS Epitopes

“…Ligand recognition mediates both internalization and signaling. Furthermore, DC-SIGN-dependent cross-presentation is enhanced by the simultaneous triggering of TLRs, being described as its ability to modify TLR signaling in a pro- or anti-inflammatory way depending on the ligand recognized. , …”

“…Furthermore, DC-SIGN-dependent cross-presentation is enhanced by the simultaneous triggering of TLRs, being described as its ability to modify TLR signaling in a pro-or anti-inflammatory way depending on the ligand recognized. 44,45 The dual role in mediating both tolerance and immune response, depending on the context, might have been exploited by pathogens and tumors that upregulate the expression of DC-SIGN ligands to take advantage of DC-SIGN-dependent tolerogenic signaling as a strategy to escape the immune system. 18,44 DC-SIGN preferentially binds to fucosylated glycans, such as blood-type Lewis antigens (Le a , Le b , Le X , Le Y , and sulfo-Le a ) 46 stimulates the TLR-induced cytokine response.…”

Integrated Network Pharmacology and Gut Microbiota Analysis to Explore the Mechanism of Sijunzi Decoction Involved in Alleviating Airway Inflammation in a Mouse Model of Asthma

“…Bacteroides have the capacity for immunomodulation, and their encoded bd oxidase renders their colonization of the intestine and positive alterations of the intestinal environment easier [ 54 ]. This microbial genus stimulates the differentiation of naïve CD4+ cells to Treg cells, increases IL-10 levels [ 62 ], and maintains the balance between Treg cells and proinflammatory Th17 and Th2 cells [ 63 ]. A reduction in the relative abundance of Bacteroides in the intestine triggers the onset of asthma [ 64 ].…”