Thymic stromal lymphopoietin and nerve growth factor itch-related pathways (TSLP and NGF pathways)

The Thymic Stromal Lymphopoietin (TSLP) and Nerve Growth Factor (NGF) pathways are two interconnected signaling systems that play a central role in the development and maintenance of chronic itch, particularly in atopic dermatitis [1, 6]. TSLP is a cytokine primarily secreted by keratinocytes that directly activates TSLP receptors on sensory neurons, triggering itch through the TRPA1 ion channel [2, 9]. NGF is a neurotrophin that contributes to pruritus by promoting the sprouting of cutaneous sensory nerves (hyperinnervation) and sensitizing these nerves by upregulating receptors such as TRPV1 [4, 17]. Together, these mediators facilitate a neuroimmune crosstalk where inflammation drives the sensation of itch, and the subsequent scratching further stimulates the release of pruritogens, creating a self-perpetuating itch-scratch cycle [13, 16]. Therapeutic strategies targeting these pathways include monoclonal antibodies like tezepelumab, which inhibits TSLP to reduce both inflammation and direct neuronal activation, and anti-NGF antibodies like tanezumab, which aim to mitigate nerve-driven hypersensitivity [10, 11]. While these targets offer promise for treating refractory pruritus, challenges such as the risk of rapidly progressive osteoarthritis with NGF inhibitors must be managed [10, 17].

Other names

TSLP and NGF itch axisTSLP and NGF signalingTLSP and NGF pathwaysThymic stromal lymphopoietin and nerve growth factor pathways

Monoclonal antibodies targeting TSLP prevent its binding to the TSLPR/IL-7Ra complex on neurons and immune cells, while anti-NGF antibodies block NGF from binding to TrkA and p75NTR, thereby reducing nerve sensitization and hyperinnervation [1, 11, 17].