TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells

Sun, Xiaotang; Hosomi, Koji; Shimoyama, Atsushi; Yoshii, Ken; Lan, Huangwenxian; Wang, Yunru; Yamaura, Haruki; Nagatake, Takahiro; Ishii, Ken J.; Akira, Shizuo; Kiyono, Hiroshi; Fukase, Koichi; Kunisawa, Jun

doi:10.1016/j.intimp.2023.109852

Cited by 5 publications

(5 citation statements)

References 70 publications

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“…Mucosal immunity and class switching to IgA + B cells are dependent on Th17 cells. In our previous reports, the stimulation of DCs with ALA stimulated the production of IL-6 and IL-23 and, consequently, enhanced the differentiation of Th17 cells from naive T cells ( 19 , 20 , 32 ). These results suggest that ALA is suitable for use as a nasal vaccine adjuvant.…”

Section: Discussionmentioning

confidence: 76%

“…In a previous study, the expression of CD80 from DCs increased the activation of T cells overall ( 44 ), whereas the expression of CD40 from DCs upregulated the differentiation of Th17 cells ( 45 ). In our previous report, ALA induced greater production of IL-6 and IL-23 than did MPLA, subsequently leading to increased differentiation of Th17 cells ( 32 ). Because the Th17 response is indispensable in the generation of mucosal immunity and secretion of IgA ( 46 , 47 ), the robust ALA-associated Th17 response may explain the superiority of ALA in intranasal immunity.…”

Section: Discussionmentioning

confidence: 84%

“…To verify the cells targeted by ALA, we sorted cells from nasal tissue according to their expression of CD45 and epithelial cell adhesion molecule (EpCAM) ( Fig. 6A ) and examined the subpopulations’ expression of TLR4, a receptor for ALA ( 22 , 32 ). We found that CD45 + immune cells showed the greatest gene expression of Tlr4 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue

Sun,

Hosomi,

Shimoyama

et al. 2023

International Immunology

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We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103− CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of ALA in nasal tissue.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 84%

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Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue

Sun,

Hosomi,

Shimoyama

et al. 2023

International Immunology

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“…Our experiments on THP‐1 cells indicated that the Ce‐MBGNs could reduce the differentiation of suspended monocytes into adherent macrophages (Figure 6a) and reduce the expression of CD86 (Figure 6c). Previous studies have shown that CD86 is a receptor on the surface of macrophages that binds to T cells, giving an initial T‐cell activation signal, generating a stimulatory effect and promoting its activation, proliferation and differentiation (Sun et al., 2023). The decrease in CD86 implies the considerable potential of Ce‐MBGNs in inhibiting M1 polarization of macrophages and immune cascade reaction, which is expected to prevent further aggravation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Anti‐inflammatory cerium‐containing nano‐scaled mesoporous bioactive glass for promoting regenerative capability of dental pulp cells

Duan,

Zheng,

et al. 2024

Int Endodontic J

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AimsThis study aimed to investigate the anti‐inflammatory and odontoblastic effects of cerium‐containing mesoporous bioactive glass nanoparticles (Ce‐MBGNs) on dental pulp cells as novel pulp‐capping agents.MethodologyCe‐MBGNs were synthesized using a post‐impregnation strategy based on the antioxidant properties of Ce ions and proposed the first use of Ce‐MBGNs for pulp‐capping application. The biocompatibility of Ce‐MBGNs was analysed using the CCK‐8 assay and apoptosis detection. Additionally, the reactive oxygen species (ROS) scavenging ability of Ce‐MBGNs was measured using the 2,7‐Dichlorofuorescin Diacetate (DCFH‐DA) probe. The anti‐inflammatory effect of Ce‐MBGNs on THP‐1 cells was further investigated using flow cytometry and quantitative real‐time polymerase chain reaction (RT‐qPCR). Moreover, the effect of Ce‐MBGNs on the odontoblastic differentiation of the dental pulp cells (DPCs) was assessed by combined scratch assays, RT‐qPCR, western blotting, immunocytochemistry, Alizarin Red S staining and tissue‐nonspecific alkaline phosphatase staining. Analytically, the secretions of tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) were detected with enzyme‐linked immunosorbent assay (ELISA).ResultsCe‐MBGNs were confirmed to effectively scavenge ROS in THP‐1‐derived macrophages and DPCs. Flow cytometry and RT‐qPCR assays revealed that Ce‐MBGNs significantly inhibited the M1 polarization of macrophages (Mφ). Furthermore, the protein levels of TNF‐α and IL‐1β were downregulated in THP‐1‐derived macrophages after stimulation with Ce‐MBGNs. With a step‐forward virtue of promoting the odontoblastic differentiation of DPCs, we further confirmed that Ce‐MBGNs could regulate the formation of a conductive immune microenvironment with respect to tissue repair in DPCs, which was mediated by macrophages.ConclusionsCe‐MBGNs protected cells from self‐produced oxidative damage and exhibited excellent immunomodulatory and odontoblastic differentiation effects on DPCs. As a pulp‐capping agent, this novel biomaterial can exert anti‐inflammatory effects and promote restorative dentine regeneration in clinical treatment. We believe that this study will stimulate further correlative research on the development of advanced pulp‐capping agents.

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“…Confirming its similarity to the extracted A. faecalis LPS, it was verified that A. faecalis lipid A 20 opposed the activity of A. faecalis LPS. Further in vivo experiments using mice demonstrated that A. faecalis lipid A 20 exhibited useful adjuvant effects without toxicity, enhancing antigenspecific IgA and IgG production and reinforcing defensive immunity via Th17 [13][14][15][16][17]. Particularly, enhanced antigen-specific IgA and IgG production was observed in mice administered with antigen and A. faecalis lipid A 20 adjuvant via intranasal administration.…”

Section: Development Of Innate Immune Regulatory Molecules Based On H...mentioning

confidence: 96%

Synthetic Study of Bio-functional Glycans

Fukase,

Shimoyama,

Manabe

2024

Modern Natural Product Synthesis

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The molecular structures responsible for the immune functions of complex glycans were unraveled by synthetic studies. We focused on developing efficient methods for synthesizing glycans and conducting diverse chemical syntheses of these compounds, to identify the molecular structures responsible for activating or modulating innate immunity. Many natural glycans contain multiple active structures, potentially leading to emergent higher-order functions through their synergistic interactions. Therefore, by employing a conjugation-based approach, we successfully created immune-regulating complex glycoconjugates.

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TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells

Cited by 5 publications

References 70 publications

Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue

Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue

Anti‐inflammatory cerium‐containing nano‐scaled mesoporous bioactive glass for promoting regenerative capability of dental pulp cells

Synthetic Study of Bio-functional Glycans

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