Juan Li's research while affiliated with Northwest University and other places

It has been found that CD226 plays an important role in regulating macrophage function, but its expression and function in macrophages during renal fibrogenesis have not been studied. Our data demonstrated that CD226 expression in macrophages was obviously upregulated in the unilateral ureteral obstruction model, while CD226 deficiency attenuated collagen deposition in renal interstitium along with fewer M1 within renal cortex and renal medulla and a lower level of proinflammatory factors compared to that of control littermates. Further studies demonstrated that Cd226−/− bone marrow–derived macrophages transferring could significantly reduce the tubular injury, collagen deposition, and proinflammatory cytokine secretion compared with that of Cd226+/+ bone marrow–derived macrophages transferring in the unilateral ureteral obstruction model. Mechanistic investigations revealed that CD226 promoted proinflammatory M1 macrophage accumulation in the kidney via suppressing KLF4 expression in macrophages. Therefore, our results uncovered a pathogenic role of CD226 during the development of chronic kidney disease by promoting monocyte infiltration from peripheral blood into the kidney and enhancing macrophage activation toward the inflammatory phenotype by suppressing KLF4 expression.

Background: Hantaan virus (HTNV) infection can cause severe hemorrhagic fever with renal syndrome (HFRS). Inflammatory monocytes (iMOs) are involved in early antiviral responses. Previous studies have found that blood iMOs numbers increase in the acute phase of HFRS. Here, we further identified the phenotypic characteristics of iMOs in HFRS and explored whether phenotypic changes in iMOs were associated with HFRS severity. Materials and methods: Blood samples from 85 HFRS patients were used for phenotypic analysis of iMOs by flow cytometry. Plasma HTNV load was determined using RT-PCR. THP-1 cells overexpressing CD226 were used to investigate the effects of CD226 on HLA-DR/DP/DQ and CD80 expression. A mouse model was used to test macrophage phenotype following HTNV infection. Results: The proportion of CD226- iMOs in the acute phase of HFRS was 66.83 (35.05-81.72) %, which was significantly higher than that in the convalescent phase (5.32 (1.36-13.52) %) and normal controls (7.39 (1.15-18.11) %) (p < 0.0001). In the acute phase, the proportion of CD226- iMOs increased more in patients with more severe HFRS and correlated positively with HTNV load and negatively with platelet count. Notably, CD226- iMOs expressed lower levels of HLA-DR/DP/DQ and CD80 than CD226+ iMOs, and overexpression CD226 could enhance the expression of HLA-DR/DP/DQ and CD80. In a mouse model, HTNV also induced the expansion of CD226- macrophages, with decreased expression of I-A/I-E and CD80. Conclusions: CD226- iMOs increased during HTNV infection and the decrease in CD226 hampered the expression of HLA-DR/DP/DQ and CD80, which may promote the immune escape of HTNV and exacerbate clinical symptoms.

It has been found that CD226 plays an important role in regulating macrophage function, but its expression and function on macrophage during renal fibrogenesis have not been studied. Our data demonstrated that CD226 expression in macrophages was obviously upregulated in the UUO model, while CD226 deficiency attenuated collagen deposition in renal inerestitum along with fewer number of M1 within renal cortex and renal medulla and a lower level of proinflammatory factors compared to control littermates. Further studies demonstrated that Cd226-/–BMDMs transferring to Cd226+/+ mice could significantly reduce the tubular injury, collagen deposition and proinflammatory cytokines secretion compared with WT-BMDMs group and WT-PBS group in adoptively transferring assay. Mechanistic investigations revealed that CD226 could suppress KLF4 expression in macrophages, which subsequently promoted more proinflammatory M1 accumulation in the kidney of WT mice than that of CD226 deficient mice. In vitro, we silenced KLF4 expression in BMDMs deriving from WT or CD226 deficient mice and the trend that CD226 promting more numbers of M1 disappeared. Therefore, our results uncover a pathogenic role of CD226 during the development of CKD by promoting monocyte infiltration from peripheral blood into the kidney and enhancing macrophage activation towards to the inflammatory phenotype by suppressing KLF4 expression.

Ulcerative colitis (UC) is a refractory and recurring inflammatory bowel disease (IBD). Monocytes and macrophages are major components of the mononuclear phagocyte system (MPS), and the balance between inflammatory monocytes and small peritoneal macrophages plays important roles in UC. However, the mechanisms governing the balance between inflammatory monocytes and small peritoneal macrophages in UC need to be clarified further. Here, we found that the expression levels of CD226 on different subsets of monocytes/macrophages are varied in UC mice. The expression levels of CD226 on patrolling monocytes (pMos) and small peritoneal macrophages (SPMs) were markedly increased, while the expression levels of CD226 on inflammatory monocytes (iMos) were decreased in UC mice. Significantly, the percentage of iMos was enhanced while the percentage of SPMs were decreased in CD226 knockout UC mice compared with that in wildtype UC mice. Moreover, CD226 deficiency suppressed the migration capacity of macrophages. Therefore, our data suggest that CD226 plays critical roles in regulating the function and balance of monocytes/macrophages in mouse UC and targeting CD226 in MPS may be developed as a potent therapy for UC.

T regulatory type 1 (Tr1) cells act as a key regulator in maintaining peripheral immune tolerance. Several costimulatory molecules for T cells have been identified in Tr1 cells, but their intrinsic functions are still unclear. Here we showed CD226 was highly expressed in Tr1 cells. CD226-deficient Tr1 cells were defective in proliferation and sensitive to apoptosis. In addition, CD226-deficient Tr1 cells showed lower inhibitory capacity of T cell proliferation and reduced IL-10 production. CD226 deficiency also inhibited Tr1 cell differentiation in vitro. When stimulated with IL-2, CD226-deficient Tr1 cells showed impaired STAT5 signaling. Therefore, our data suggest CD226 might play an important role in Tr1 cell homeostasis, function and differentiation. This study facilitates further biological characterization of this regulatory T cell subset.

Cluster of differentiation 226 (CD226) molecules play a crucial role in the activation of effector CD4⁺ T cells during the immune response process, but a cell-intrinsic function of CD226 in CD4⁺ T subsets is not clear. In this study, we showed that Cd226−/− mice were resistant to myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35−55)-induced experimental autoimmune encephalomyelitis (EAE) with highly expressed IL-10⁺CD4⁺ T cells and downregulated IL-17A⁺CD4⁺ T cells when compared with wild-type (WT) mice. Th17 cell infiltration into the central nervous system (CNS) was largely decreased in the absence of CD226 during EAE. CD226 deficiency facilitated the proliferation of regulatory T cells (Tregs), with increased numbers of Tregs observed in EAE mice, and supported the elevated induced regulatory T cell (iTregs) proliferation in vitro. The Akt and Erk signaling pathways were shown to be involved in Cd226−/− Treg proliferation and function in vivo and in vitro. These findings collectively indicate that CD226 is a key molecule regulating the Treg-mediated suppression of autoimmune responses by inhibiting Treg proliferation. Thus, the results of this study identify additional mechanisms by which CD226 regulates Treg functions in EAE and supports the potential therapeutic effects of anti-CD226 molecules on autoimmune diseases.