TY - JOUR
T1 - Azithromycin targets the CD27 pathway to modulate CD27hi T-lymphocyte expansion and type-1 effector phenotype
AU - Ansari, Abdul Wahid
AU - Jayakumar, Manju Nidagodu
AU - Ahmad, Fareed
AU - Venkatachalam, Thenmozhi
AU - Salameh, Laila
AU - Unnikannan, Hema
AU - Raheed, Thesni
AU - Mohammed, Abdul Khader
AU - Mahboub, Bassam
AU - Al-Ramadi, Basel K.
AU - Hamid, Qutayba
AU - Steinhoff, Martin
AU - Hamoudi, Rifat
N1 - Publisher Copyright:
Copyright © 2024 Ansari, Jayakumar, Ahmad, Venkatachalam, Salameh, Unnikannan, Raheed, Mohammed, Mahboub, Al-Ramadi, Hamid, Steinhoff and Hamoudi.
PY - 2024
Y1 - 2024
N2 - Macrolide antibiotic azithromycin is widely used in clinical practice to treat respiratory tract infections and inflammatory diseases. However, its mechanism of action is not fully understood. Given the involvement of the CD27 pathway in the pathophysiology of various T-lymphocyte-mediated inflammatory, autoimmune, and lymphoproliferative diseases, we examined the impact of AZM on CD27 regulation and potential consequences on CD4+ and CD8+ T-cell phenotypes. Using cellular immunology approaches on healthy donors’ peripheral blood mononuclear cells, we demonstrate AZM-mediated downregulation of surface CD27 expression as well as its extracellular release as soluble CD27. Notably, AZM-exposed CD27high (hi) cells were defective in their ability to expand compared to CD27intermediate (Int) and CD27low (lo) subsets. The defective CD27hi subset expansion was found to be associated with impaired cell proliferation and cell division. At the molecular level, the CD27hi subset exhibited lower mTOR activity than other subsets. Functionally, AZM treatment resulted in marked depletion of helper CD4+ (Th1) and cytotoxic CD8+ T-lymphocyte (Tc1)-associated CXCR3+CD27hi effector cells and inhibition of inflammatory cytokine IFN-γ production. These findings provide mechanistic insights on immunomodulatory features of AZM on T-lymphocyte by altering the CD27 pathway. From a clinical perspective, this study also sheds light on potential clinical benefits observed in patients on prophylactic AZM regimens against various respiratory diseases and opens avenues for future adjunct therapy against Th1- and Tc1-dominated inflammatory and autoimmune diseases.
AB - Macrolide antibiotic azithromycin is widely used in clinical practice to treat respiratory tract infections and inflammatory diseases. However, its mechanism of action is not fully understood. Given the involvement of the CD27 pathway in the pathophysiology of various T-lymphocyte-mediated inflammatory, autoimmune, and lymphoproliferative diseases, we examined the impact of AZM on CD27 regulation and potential consequences on CD4+ and CD8+ T-cell phenotypes. Using cellular immunology approaches on healthy donors’ peripheral blood mononuclear cells, we demonstrate AZM-mediated downregulation of surface CD27 expression as well as its extracellular release as soluble CD27. Notably, AZM-exposed CD27high (hi) cells were defective in their ability to expand compared to CD27intermediate (Int) and CD27low (lo) subsets. The defective CD27hi subset expansion was found to be associated with impaired cell proliferation and cell division. At the molecular level, the CD27hi subset exhibited lower mTOR activity than other subsets. Functionally, AZM treatment resulted in marked depletion of helper CD4+ (Th1) and cytotoxic CD8+ T-lymphocyte (Tc1)-associated CXCR3+CD27hi effector cells and inhibition of inflammatory cytokine IFN-γ production. These findings provide mechanistic insights on immunomodulatory features of AZM on T-lymphocyte by altering the CD27 pathway. From a clinical perspective, this study also sheds light on potential clinical benefits observed in patients on prophylactic AZM regimens against various respiratory diseases and opens avenues for future adjunct therapy against Th1- and Tc1-dominated inflammatory and autoimmune diseases.
KW - CD27 subset
KW - CXCR3
KW - T-lymphocytes
KW - azithromycin
KW - inflammation
KW - mTOR
KW - type-1 immunity
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U2 - 10.3389/fimmu.2024.1447625
DO - 10.3389/fimmu.2024.1447625
M3 - Article
C2 - 39211048
AN - SCOPUS:85202768797
SN - 1664-3224
VL - 15
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1447625
ER -