HMGB1 released from intestinal epithelia damaged by cholera toxin adjuvant contributes to activation of mucosal dendritic cells and induction of intestinal cytotoxic T lymphocytes and IgA

Abstract

Cholera toxin (CT) is a potent mucosal adjuvant and oral administration of ovalbumin (OVA) antigens plus CT induces OVA-specific CD8+ cytotoxic T lymphocytes (CTLs) and IgA production in intestinal mucosa. However, the mechanisms of induction of these immune responses remain unknown. Intestinal OVA-specific CD8+ CTLs were not induced by oral administration of the CT active (CTA) or CT binding (CTB) subunit as an adjuvant and CD11c+ DCs were involved in cross-priming of intestinal CTLs. CD8+CD103+CD11c+CD11b−DCs and DCIR2+CD103+CD11c+CD11b+ DCs were distributed in the intestinal lamina propria and mesenteric lymph nodes, both DC subsets expressed DEC-205, and the expression of co-stimulatory molecules such as CD80 and CD86 was enhanced in both DC subsets after oral administration of intact CT but not the CTA or CTB subunit. Intestinal DCs activated by the oral administration of OVA plus CT cross-presented OVA antigens and DCs that captured OVA antigen through DEC-205, but not DCIR2, could cross-present antigen. We found that oral administration of intact CT, but not the CTA or CTB subunit, enhanced cell death, cytoplasmic expression of high-mobility group box 1 protein (HMGB1) in epithelial cell adhesion molecule (EpCAM)+CD45− intestinal epithelial cells (IECs), and HMGB1 levels in fecal extracts. HMGB1 dose-dependently enhanced the expression of CD80 and CD86 on DCs in vitro, and intravenous or oral administration of glycyrrhizin, an HMGB1 inhibitor, significantly suppressed activation of mucosal DCs and induction of intestinal OVA-specific CTLs and IgA by oral CT administration. These results showed that oral administration of intact CT triggers epithelial cell death in the gut and the release of HMGB1 from damaged IECs, and that the released HMGB1 may mediate activation of mucosal DCs and induction of CTLs and IgA in the intestine.

Inflammasomes as Targets for Adjuvants

“…As a result, a pyrin receptor interacts with modified RhoA and triggers inflammasome self-assembly [89]. The efficacy of cholera toxin B as an adjuvant was demonstrated in a mouse model [90]. This adjuvant was able to increase the circulating IgG titers as well as mucosal IgA levels.…”

Induction of systemic immunity through nasal-associated lymphoid tissue (NALT) of mice intranasally immunized with Brucella abortus malate dehydrogenase-loaded chitosan nanoparticles

“…Recent findings have highlighted that HMGB1 pathway is crucial not only for the inducing inflammatory responses of upper respiratory tract (URT) but also for mediating DCs maturation and activation [36][37][38][39]. HMGB1 is a archetypical alarmin that can act as a danger signal that initiates the host defense response [40].…”

“…In our results, HMGB1 pathway via TLR4 as well as IL-6 signaling and DCs maturation were predicted to be activated in CNs-Mdhimmunized group. Another study showed that oral administration of a representative mucosal adjuvant, cholera toxin, triggers the release of HMGB1 from damaged intestinal epithelial cells, and that the released HMGB1 may mediate the activation of mucosal DCs, cytotoxic T lymphocytes and IgA production in the intestine [37]. Although the relationship between innate immune pathway and production of IgA is still not well defined, we reasonably assume that activated HMGB1 signaling pathways with IL-6 signaling and DCs maturation are shown by CNs-Mdh due to the relevance of followed production of IgA.…”

The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

“…HMGB1 is critical for CXCL12 activity, which attracts myeloid-derived cells, thereby promoting recruitment and motility of leukocytes [ 119 ]. The Hp91 sequence within the B-Box domain of HMGB1 is required for DC activation; via this domain, HMGB1 enters DCs in a clathrin- and dynamin-dependent manner [ 131 ]. Hp91-mediated DC activation is dependent on TLR4, MyD88 and IFNαβR and it is mediated by NF-κB and p38 MAPK cascades [ 131 , 132 ].…”