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The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducting resolution of inflammation

ABSTRACT: Here we show that soluble CD83 induces resolution of inflammation in the antigen-induced arthritis (AIA) model. Joint swelling as well as arthritis related expression levels of IL‐1β, IL‐6, RANKL, MMP9 and OC‐Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP+ osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA-sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as OC-STAMP, MMP9, NFATC1, Ctsk and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g. Mrc1/2, Marco, Klf4 and Mertk, were upregulated. Interestingly, also members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were highly induced by sCD83 also in samples derived from RA patients. Finally, we elucidated the sCD83-induced signalling cascade, downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex, using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signalling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce resolution of inflammation and to prevent bone erosion in autoimmune arthritis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207872 | GEO | 2022/07/13

REPOSITORIES: GEO

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Project description:Toll-like receptors (TLRs), a family of pattern recognition receptors, bind microbial and host-derived molecules, leading to intracellular signaling and activation of host innate immune responses. TLR4 is unique in that ligand-mediated activation initiates two signaling cascades: the MyD88-dependent pathway, localized to the cell membrane, elicits rapid MAP kinase and NF-κB activation, and the TRIF-dependent pathway, localized to TLR4-containing endosomes, results in IRF-3 activation. Previous studies have associated adjuvanticity with the TRIF pathway. Gram-negative LPS is a potent TLR4 agonist, and structurally related molecules also signal through TLR4 to different extents. Herein, we compared two synthetic, non-toxic lipid A analogs used previously as vaccine adjuvants, monophosphoryl lipid A (PHAD®, sMPL) and E6020, for their capacity to activate TLR4-mediated innate immune responses. In primary mouse macrophages, high dose sMPL activates the MyD88-dependent signaling equivalently to E6020. In contrast to sMPL, E6020 exhibits robust activation of the TRIF pathway, including TLR4 internalization and IRF-3-dependent transcription, at all doses examined. Eritoran, a TLR4/MD2 antagonist, competitively inhibited sMPL more strongly than E6020. Despite these differences, sMPL and E6020 adjuvants induced antibody responses to a similar level and with balanced Ig isotypes, in two separate mouse immunization models. However, E6020 induced superior non-specific protection in a model of Streptococcus pneumoniae infection, compared to sMPL, which correlates with the activation of reactive nitrogen and oxygen species. These data provide evidence that a TRIF bias is not necessarily predictive of superior adjuvanticity, but may activate stronger innate defenses from infection. TLR4 is unique among TLRs that it stimulates both the MyD88- and TRIF-dependent pathways (reviewed in Takeda K and Akira S, 2004, Semin Immunol). To compare the relative stimulatory capacities of two synthetic TLR4 agonist adjuvants, PHAD® (sMPL; Avanti Polar Lipids LLC) and E6020 (Eisai, Inc), we performed microarray analysis of primary thioglycollate-elicited mouse peritoneal macrophages that were either cultured in media alone (control) or stimulated with 100 ng/mL (57.3 uM sMPL, 61.6 uM E6020) of the TLR4 agonists for two hours. Total RNA was extracted from three biological repicates (numbered 1-3) per treatment, and the transcriptomes analyzed individually by whole transcriptome microarray (Affymetrix Clariom D). Of the differentially expressed genes (DE genes; average of three replicates greater or equal to 2-fold difference in any comparison of treatments and false discovery rate below 0.05) almost 94% were protein-coding genes (includes those listed as either protein-coding or complex in the database), on which we focused for further analysis. sMPL induced expression of 155 protein-coding genes, including those that encode IL-1beta, TNF-alpha, Cxcl1 and Cxcl2--proteins that are associated with classic macrophage activation and are essential for inducing fever and attracting neutrophils. sMPL suppressed 15 protein-coding genes. In contrast, E6020 induced expression of 413 protein-coding genes and suppressed 88 protein-coding genes, which included all but one of the sMPL-regulated protein-coding genes. The majority of the genes induced by E6020, but not sMPL, are associated with Type I IFN expression (reference: Interferome.org database). This interferon signature points to stronger activation of the TRIF/IRF3 pathway in E6020-treated macrophages and includes genes that are secondarily induced by Type I IFNs. Similar expression of MyD88 dependent genes Il1b, Il10, and Tnf, and differential expression of TRIF-dependent genes Ifnb1, Cxcl10, and Ccl5 between the two synthetic agonists was confirmed by qRT-PCR.

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The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducting resolution of inflammation

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