Kai Huang1, Shuyu Ge2. 1. Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, China. 2. Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, China. zjhzsltd@sina.com.
Abstract
BACKGROUND: Chronic osteomyelitis is associated with the immune suppression. CD4(+)CD25(+) FOXP3(+) regulatory T cells (Tregs) play a key role in the peripheral tolerance to prevent immune responses to self-antigens and allergens. Evidence has suggested that the accumulation and activity of Tregs are regulated by chemokine family member CXCL10 and its receptor CXCR3 in human atherosclerotic lesions. This study aimed to investigated the effect of CXCL4, a member of chemokine family, on Tregs, and the underlying mechanisms. METHODS: CD4+ T cells were isolated from peripheral blood of patients with chronic osteomyelitis or healthy controls. Anti-CXCL4 antibody and recombinant CXCL4 protein were used for treatment. The expression of forkhead box P3 (FOXP3), cytotoxic T lymphocyte antigen-4 (CTLA-4) and phosphorylated signal transducer and activator of transcription 5 (STAT5) were measured to assess the mechanism. STAT5 inhibitor (IST5-002) was used to retard STAT5 pathway. RESULTS: We found that serum concentration of CXCL4 in chronic osteomyelitis was significantly enhanced. Through the prevention of STAT5 activity, CXCL4 antibody could inhibit the protein expression of CXCL4, CXCR3, FOXP3, CTLA-4 and phosphorylated-STAT5, as well as decrease the percentage of Tregs in CD4+ T cells. Conversely, recombinant CXCL4 protein resulted in the opposite in CD4+ T cells from healthy controls, obviously enhancing Tregs percentage and promoting STAT5 activation, which were significantly reversed by an STAT5 inhibitor. CONCLUSIONS: CXCL4 antagonism inhibited Tregs percentage and Tregs-associated proteins within CD4+ T cells from chronic osteomyelitis patients via blocking the STAT5 pathway.
BACKGROUND:Chronic osteomyelitis is associated with the immune suppression. CD4(+)CD25(+) FOXP3(+) regulatory T cells (Tregs) play a key role in the peripheral tolerance to prevent immune responses to self-antigens and allergens. Evidence has suggested that the accumulation and activity of Tregs are regulated by chemokine family member CXCL10 and its receptor CXCR3 in humanatherosclerotic lesions. This study aimed to investigated the effect of CXCL4, a member of chemokine family, on Tregs, and the underlying mechanisms. METHODS:CD4+ T cells were isolated from peripheral blood of patients with chronic osteomyelitis or healthy controls. Anti-CXCL4 antibody and recombinant CXCL4 protein were used for treatment. The expression of forkhead box P3 (FOXP3), cytotoxic T lymphocyte antigen-4 (CTLA-4) and phosphorylated signal transducer and activator of transcription 5 (STAT5) were measured to assess the mechanism. STAT5 inhibitor (IST5-002) was used to retard STAT5 pathway. RESULTS: We found that serum concentration of CXCL4 in chronic osteomyelitis was significantly enhanced. Through the prevention of STAT5 activity, CXCL4 antibody could inhibit the protein expression of CXCL4, CXCR3, FOXP3, CTLA-4 and phosphorylated-STAT5, as well as decrease the percentage of Tregs in CD4+ T cells. Conversely, recombinant CXCL4 protein resulted in the opposite in CD4+ T cells from healthy controls, obviously enhancing Tregs percentage and promoting STAT5 activation, which were significantly reversed by an STAT5 inhibitor. CONCLUSIONS:CXCL4 antagonism inhibited Tregs percentage and Tregs-associated proteins within CD4+ T cells from chronic osteomyelitispatients via blocking the STAT5 pathway.
Entities:
Keywords:
CXCL4; Chronic osteomyelitis; regulatory T cells (Tregs); signal transducer and activator of transcription 5 pathway (STAT5 pathway)
Authors: Michael Radzieta; Matthew Malone; Mehtab Ahmad; Hugh G Dickson; Saskia Schwarzer; Slade O Jensen; Lawrence A Lavery Journal: Front Microbiol Date: 2022-08-01 Impact factor: 6.064