The immune receptors TLR4 and SLAMF1 regulate TNF release by human
metapneumovirus in human macrophages
#MMPMID41346628
Sæterhaug Bye K
; Rian K
; Ryan L
; Espevik T
; Anthonsen MW
; Yurchenko M
Front Immunol
2025[]; 16
(?): 1697494
PMID41346628
show ga
BACKGROUND: Human metapneumovirus (HMPV) is a major cause of acute respiratory
disease in children, the elderly, and immunocompromised individuals. While
pro-inflammatory cytokines and type I interferons (IFNs) are important for
antiviral defense, excessive tumor necrosis factor (TNF) is associated with
severe disease in HMPV and other respiratory infections. Hence, defining
regulatory mechanisms by which HMPV induces TNF and IFN-? is important for
therapeutic strategies in airway disease. The immunoregulatory receptors
Toll-like receptor (TLR)4 and signaling lymphocytic activation molecule family 1
(SLAMF1) mediate TNF and IFN-? expression in response to LPS and Gram-negative
bacteria, but their involvement in HMPV-stimulated cytokine expression is
unclear. METHODS: We investigated the kinetics of TNF and IFNB1 expression in
human monocyte-derived macrophages (MDMs) and THP-1 macrophage-like cells. The
impact of SLAMF1 and TLR4 on TNF, IFNB1, and p38 MAPK was determined after their
overexpression or knockout in THP-1 cells or silencing in MDMs. RESULTS: TLR4
knockout reduced TNF but not IFNB1 induced by HMPV, whereas SLAMF1 silencing
reduced both cytokines. Overexpression of TLR4 or SLAMF1 enhanced p38 MAPK
activation and TNF secretion, while silencing of TLR4 or SLAMF1 reduced p38 MAPK
activation and TNF secretion. Pharmacological inhibition of p38 MAPK reduced both
TNF and IFNB1, confirming its essential role in cytokine induction. CONCLUSIONS:
Together, our findings identify TLR4 and SLAMF1 as key regulators of early
HMPV-induced inflammation via p38 MAPK. SLAMF1 additionally influences IFN-?
responses and appears to affect viral replication dynamics. These insights
suggest that targeting SLAMF1-TLR4 signaling may offer a therapeutic strategy to
limit TNF-driven pathology in HMPV infection.
free
free
free
