Toll-like receptor 4–KH-type splicing regulatory protein–let-7 microRNA signaling pathway (TLR4–KSRP–let-7 axis)

The TLR4–KSRP–let-7 microRNA processing pathway is a sophisticated regulatory circuit in immune cells that controls the magnitude and duration of the inflammatory response [1]. Toll-like receptor 4 (TLR4) serves as the primary sensor for bacterial lipopolysaccharides, triggering downstream signaling upon activation. A key component of this response is the KH-type splicing regulatory protein (KSRP), an RNA-binding protein that facilitates the maturation of the let-7 microRNA family [1, 2]. KSRP binds specifically to the terminal loops of let-7 precursors, enhancing their processing by the Drosha and Dicer complexes. Once mature, let-7 microRNAs act as post-transcriptional repressors of several pro-inflammatory cytokines and the TLR4 receptor itself [3]. This interaction creates a negative feedback loop essential for preventing excessive inflammation and promoting the resolution of the immune response. Dysfunction in this axis is linked to various pathologies, including sepsis, chronic inflammatory disorders, and oncogenesis. Pharmacological modulation of this pathway, such as through TLR4 inhibitors or microRNA-based therapeutics, represents a promising approach for treating immune-mediated diseases. [1] Trabucchi M, et al. Nature. 2009;459(7249):1010-1014. [2] O'Neill LA, et al. Nat Rev Immunol. 2011;11(3):163-175. [3] Chen XM, et al. J Biol Chem. 2007;282(39):28721-28728.

Other names

TLR4-KSRP-let-7 pathwayTLR4-mediated let-7 biogenesisKSRP-regulated microRNA processing axisTLR4-KSRP-miRNA immune regulatory circuit

Modulation of TLR4 signaling and KSRP-mediated microRNA maturation to regulate pro-inflammatory gene expression through post-transcriptional silencing.