Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis

Abstract

Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggesting that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD, although whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analog of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice). Methods We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3 T3) in vitro. Results When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3 T3. Conclusion We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD.

Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation

“…6 F). CCL1 and CCL18 produced by macrophages are known human CCR8 ligands with high affinity [ 23 ], and murine Ccl8 is a functional analog of human CCL18 [ 24 ]. Oxamate treatment decreased Ccl1 and Ccl8 expressions of tumor tissues from glioma implanted nude mice (Fig.…”

Potential roles of non-lymphocytic cells in the pathogenesis of IgG4-related disease

“…Furukawa S et al found that CCL18 was co-localized with massive infiltrated M2 in IgG4-RD affected tissues, and positively associated with the fibrosis scores (16). Honda F et al confirmed that blocking CCL8 (analog of human CCL18) in LAT Y136F knock-in mice (an animal model of IgG4-RD) alleviated the degree of fibrosis in affected salivary glands, and further in vitro assays revealed that CCL8 could directly stimulate collagen production in mouse fibroblasts (17). M2 can also induce plasma cell recruitment by secreting tumor necrosis factor ligand superfamily member 13(TNFSF13/APRIL) and further promote fibrogenesis (18).…”

Defective LAT signalosome pathology in mice mimics human IgG4-related disease at single-cell level

“…2-mo-old Lat Y136F mice develop systemic autoimmunity as documented by the presence of autoantibodies directed to DNA and kidney and salivary gland autoantigens ( Genton et al, 2006 ; Sommers et al, 2002 ). Dense infiltrates made of CD4 + T cells and IgG1-producing plasma cells (PC) are found in the lung, liver, salivary glands, pancreas, kidney, and dura mater of Lat Y136F mice with occasional fibrosis and eosinophilia ( Aguado et al, 2002 ; Cui et al, 2019 ; Genton et al, 2006 ; Honda et al, 2021 ; Waseda et al, 2021 ; Yamada et al, 2018 ). In view of this spectrum of histopathological manifestations and considering that mouse IgG1 constitutes the homologue of human IgG4, it has been suggested that the Lat Y136F DLSP constitutes a mouse model of human IgG4-related disease (IgG4-RD; Yamada et al, 2018 ), a fibro-inflammatory condition originally characterized by high levels of IgG4.…”