Neutrophilic CXCR2 and BLT1: Therapeutic Targets for Acute Itch and Eczema

The inventors have demonstrated that CXCL1, a neutrophil chemoattractant and natural ligand for CXCR2, robustly induces itch when injected subcutaneously in mice. CXCL1 is the mouse homologue for human Interleukin-8, which is increased in several inflammatory skin disorders, including psoriasis and atopic dermatitis. The inventors have demonstrated that IL8 is increased in primary human keratinocytes upon activation by multiple itch agonists. Importantly, CXCL1-induced itch is entirely dependent on neutrophils. Further, mice lacking TRPA1 show reduced itch responses to CXCL1, and TRPA1 has previously been implicated in several forms of histamine-independent acute and chronic itch. In addition, loss of TRPA1 results in reduced CXCL1 expression in skin. Blocking/ablation of the high-affinity LTB4 receptor, BLT1, also results in reduction of CXCL1-induced itch. Both LTB4 and reactive oxygen species (ROS) are produced by neutrophils and have been proposed to directly activate neurons and induce itch. The inventors show that neutrophils also play a key role in chronic itch. In a mouse model of atopic dermatitis, depletion of neutrophils during induction of itch drastically reduces itch and inflammatory responses. The inventors also show that CXCL1 is increased in multiple mouse models of chronic itch, and LTB4 is increased in skin of mice with atopic dermatitis. They propose that neutrophils activate sensory neurons through the ion channel TRPA1 in a CXCL1/BLT1/LTB4-dependent fashion. Javed Afzal jafzal@berkeley.edu 510-643-7201

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