MEK Inhibitors and Toll-like Receptor Signaling: Implications for Infection and Inflammation

Toll-like receptors (TLRs) are essential components of the innate immune system that enable host cells to sense microbial and endogenous danger signals and to initiate inflammatory and antimicrobial responses. Activation of TLRs triggers complex intracellular signaling networks that culminate in the induction of pro-inflammatory cytokines, type I interferons, and co-stimulatory molecules. In addition to the well-characterized nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, mitogen-activated protein kinases (MAPKs) play a critical modulatory role in TLR signaling. MAPK/ERK kinase (MEK) inhibitors were originally developed for the treatment of cancer and are widely used in clinical oncology. Accumulating evidence indicates that pharmacological inhibition of MEK/extracellular signal regulated kinase (ERK) signaling profoundly affects immune cell function and TLR-driven responses. Depending on timing, dose, and disease context, MEK inhibition can attenuate excessive inflammation but may also interfere with protective host defense mechanisms. This duality highlights the context-dependent role of MEK/ERK signaling in infection and inflammation. In this review, I summarize current knowledge on the integration of MEK/ERK signaling into TLR-mediated innate immune responses and discuss the immunological consequences of MEK inhibition in infectious and inflammatory settings. By synthesizing mechanistic and translational studies, I aim to provide a framework for understanding MEK inhibitors as immune modulators rather than as broadly acting anti-inflammatory agents.