C-type lectin receptor Dectin3 deficiency balances the accumulation and function of FoxO1-mediated LOX-1+ M-MDSCs in relieving lupus-like symptoms

Abstract

Recent studies indicate that Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) can function as the signal of pattern recognition receptors, which play a pivotal role in the pathogenesis of the autoimmune disease. Systemic lupus erythematosus (SLE) is a classic autoimmune disease. Previous reports mainly focused on the potential role of TLRs in regulating the development of SLE, but little is known about the role of CLRs in the progression of SLE. Our previous studies showed that the inflammation-mediated accumulation of myeloid-derived suppressor cells (MDSCs) including granulocytic (G-MDSCs) and monocytic (M-MDSCs) participated in the pathogenesis of lupus. Mice deficient in Card9 (the downstream molecule of CLRs) were more susceptible to colitis-associated cancer via promoting the expansion of MDSCs. Whether the abnormal activation of CLRs regulates the expansion of MDSCs to participate in the pathogenesis of lupus remains unknown. In the present study, the expressions of CLRs were examined in both SLE patients and mouse models, revealing the expression of Dectin3 was positively correlated with SLEDAI. Dectin3 deficiency retarded the lupus-like disease by regulating the expansion and function of MDSCs. The mechanistic analysis revealed that Dectin3 deficiency promoted FoxO1-mediated apoptosis of MDSCs. Syk-Akt1-mediated nuclear transfer of FoxO1 increased in Dectin3-deficient MDSCs. Notedly, the accumulation of M-MDSCs mainly decreased in Dectin3−/− lupus mice, and the nuclear transfer of FoxO1 negatively correlated with the expression of LOX-1 on M-MDSCs. The silencing of FoxO1 expression in Dectin3−/− mice promoted the expansion of LOX-1+ M-MDSCs in vivo, and LOX-1+ M-MDSCs increased the differentiation of Th17 cells. Both LOX-1 expression on M-MDSCs and Dectin3 expression on MDSCs increased in patients with SLE. These data indicated that increased LOX-1+ M-MDSCs were related to the exacerbation of SLE development and might be potential target cells for the treatment of SLE.

IGF1R signalling is a guardian of self-tolerance restricting autoantibody production

“…As predicted by the non-inflammatory environment, the IGF1R lo CD14 + cells produced higher levels of IL10 and IL1β as judged by RNA-seq and by protein cytokine levels in cell culture supernatants ( Figures 4C, D ), a sign of M2-type macrophages. In addition to cytokines, IGF1R lo CD14 + cells expressed higher levels of MHCII receptors HLA-DQA1, HLA-DPA1 and HLA-DRB1, and in C-type lectin binding receptors including the macrophage scavenger receptor 1 (MSR1) and the mannose receptor 1 (MRC1) directly interacting with T cells ( 47 ) ( Figure 4D ), and CLEC6A/DCIR2, CLEC4E/MINCLE, CLEC5A/MDL1, CLEC12A/MICL, CLEC4A/DCIR ( Figure 4E ) essential for immunoregulation of T and B cell function ( 48 – 51 ).…”

“…Similar to our findings, FOXO1 deficient peripheral B cells have been shown to express low levels of CD62L and to fail class-switch recombination ( 41 , 60 ). Additionally, FOXO1 silencing promoted monocyte expansion, which was concomitant with exacerbation of SLE-like autoimmunity ( 51 ). Analogously, IGF1R lo CD14 + cells from RA patients had low expression of FOXO family proteins, which coincided with a higher frequency of autoantibody production in those patients, which leads us to believe that IGF1R dependent activity of FOXO in APC was an important mechanism counteracting break of immunological tolerance.…”

“…The molecular nature of the direct interaction between MHCII + APC and B cells has not been elucidated in depth and requires further studies. The C-type lectins upregulated in IGF1R lo CD14 + cells of RA patients and in APC after IGF1R inhibition in mice and their emerging immune regulatory function ( 47 , 50 , 51 ) are the candidate mediators of such an interaction.…”

The Role of C-Type Lectin Receptor Signaling in the Intestinal Microbiota-Inflammation-Cancer Axis

“…In addition to deteriorating experimental autoimmune encephalomyelitis ( 110 ) and systemic lupus erythematosus ( 111 ), Dectin-3 was initially found a limited role in regulating intestinal immunity ( 112 ), while later research revealed that Dectin-3 was also significant in intestinal homeostasis through interplaying with commensal fungi. The deficiency of Dectin-3 leads to more susceptibility to DSS-induced mouse colitis, with an obviously increase of specific fungal burden and microbial translocation, especially a common commensal Candida tropicalis ( 113 ).…”

Antifungal immunity mediated by C-type lectin receptors may be a novel target in immunotherapy for urothelial bladder cancer

“…One is similar to what we have discussed above: the regulation of the production of certain functional cytokines, such as IFN-γ, TGF-β, and IL-27, could increase PD-L1 mRNA expression ( 104 ), which may partly explain the mechanism of PD-L1 upregulation in the regulation of fungi–CLR interaction. The other possible direction is from the expression characteristics of CLRs, which are mainly expressed in innate immune cells, such as macrophages, dendritic cells, monocytes, and MDSCs ( 105 , 106 ). It is worth noting that, in addition to tumor cells, these myeloid-derived innate immune cells can also express PD-L1 in the tumor microenvironment ( 107 , 108 ).…”