Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

Abstract

SummaryExposure of bone‐marrow‐derived dendritic cells (BMDC) to high‐dose ultrapure lipopolysaccharide for 24 hr (LPS‐primed BMDC) enhances their potency in preventing inter‐photoreceptor retinoid binding protein: complete Freund's adjuvant‐induced experimental autoimmune uveoretinitis (EAU). LPS‐primed BMDC are refractory to further exposure to LPS (= endotoxin tolerance), evidenced here by decreased phosphorylation of TANK‐binding kinase 1, interferon regulatory factor 3 (IRF3), c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase as well as impaired nuclear translocation of nuclear factor κB (NF‐κB) and IRF3, resulting in reduced tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐12 and interferon‐β secretion. LPS‐primed BMDC also show reduced surface expression of Toll‐like receptor‐4 and up‐regulation of CD14, followed by increased apoptosis, mediated via nuclear factor of activated T cells (NFATc)‐2 signalling. LPS‐primed BMDC are not only homotolerant to LPS but are heterotolerant to alternative pathogen‐associated molecular pattern ligands, such as mycobacterial protein extract (Mycobacterium tuberculosis). Specifically, while M. tuberculosis protein extract induces secretion of IL‐1β, TNF‐α and IL‐6 in unprimed BMDC, LPS‐primed BMDC fail to secrete these cytokines in response to M. tuberculosis. We propose that LPS priming of BMDC, by exposure to high doses of LPS for 24 hr, stabilizes their tolerogenicity rather than promoting immunogenicity, and does so by multiple mechanisms, namely (i) generation of tolerogenic apoptotic BMDC through CD14:NFATc signalling; (ii) reduction of NF‐κB and IRF3 signalling and downstream pro‐inflammatory cytokine production; and (iii) blockade of inflammasome activation.

Coronary artery bypass grafting is associated with immunoparalysis of monocytes and dendritic cells

“…While immunoparalysis has been reported previously in mice spleen–derived DC and in a model of differentiated MoDC from sepsis patients following secondary insult, understanding of DC immunoparalysis is limited. In the model of bacterial infection, DC HLA‐DR expression was down‐regulated and had a reduced capacity to respond to LPS during CABG and throughout the entire post‐operative period (Figure 3A).…”

“…Persistent imbalance of immune homeostasis can result in a state of overwhelming immunosuppression and consequently immunoparalysis . Immunoparalysis is hypothesized to be a protective adaptation to an overwhelming pro‐inflammatory response rendering key cells of the immune response unresponsive to a secondary insult (eg LPS) .…”

“…Persistent imbalance of immune homeostasis can result in a state of overwhelming immunosuppression and consequently immunoparalysis . Immunoparalysis is hypothesized to be a protective adaptation to an overwhelming pro‐inflammatory response rendering key cells of the immune response unresponsive to a secondary insult (eg LPS) . When cells become paralysed, their capacity to respond appropriately to additional stimulus is reduced and is characterized by reduced monocyte HLA‐DR surface expression and TNF‐α production .…”

“…An imbalance in immune homeostasis due to SIRS and/or CARS may increase the risk of CABG patients developing post‐operative infection, particularly when CARS dominates over SIRS . An imbalance in immune homeostasis can also lead to cell immunoparalysis, which renders the immune system unresponsive to a secondary insult (eg inflammation or infection) . Immunoparalysis or dysfunction of cells involved in the immune response could have detrimental implications for the patient, therefore restoring immune homeostasis is vital to prevent adverse patient outcomes .…”

Autoimmunity, Autoinflammation, and Infection in Uveitis

“…80 In contrast, tolerogenic DC, which protect experimental mice against EAU, specifically fail to generate IL-1 when activated by MTb. 81 MTb is believed to have infected up to a third of the world's population, the majority of whom remain latently infected, with a significant mortality rate. 82 MTb is a major cause of uveitis in humans, both in developed and in developing countries, 83,84 and presents in a large variety of clinical phenotypes, some of which are included in the category undifferentiated or noninfectious, such as atypical serpiginous choroiditis.…”