Mechanisms and treatments of neuropathic itch in a mouse model of lymphoma

Abstract

Our understanding of neuropathic itch is limited, due to the lack of relevant animal models. Patients with cutaneous T-cell lymphoma (CTCL) suffer from severe itching. Here we characterize a mouse model of chronic itch with remarkable lymphoma growth, immune cell accumulation, and persistent pruritus. Intradermal CTCL inoculation produces time-dependent changes in nerve innervations in lymphoma-bearing skin. In the early-phase (20 days), CTCL causes hyper-innervations in the epidermis. Chronic itch is associated with loss of epidermal nerve fibers in the late-phases (40 and 60 days). Notably, we found nerve innervations in mouse lymphoma and CTCL patients with mycosis fungoides. Blockade of C-fibers reduced pruritus at early-and late-phases, whereas blockade of A-fibers only suppressed late-phase itch. Intrathecal gabapentin injection reduced late-phase but not early-phase pruritus. IL-31 is upregulated in mouse lymphoma, while its receptor Il31ra was persistently upregulated in Trpv1-expressing sensory neurons in CTCL mice. Intratumoral anti-IL-31 treatment effectively suppressed CTCL-induced scratching and alloknesis. Finally, intrathecal administration of TLR4 antagonist attenuated pruritus in early and late phases and in both sexes. Collectively, we have established a mouse model of neuropathic and cancer itch with relevance to human disease. Our findings also suggest distinct mechanisms underlying acute, chronic, and neuropathic itch.

Clinical Features of Cutaneous Paraneoplastic Syndromes in Hodgkin Lymphoma

“… 4 The mechanism of paraneoplastic pruritus in the setting of underlying malignancy is likely multifactorial, including hypersensitivity to tumor-specific antigens, eosinophilia, and production of histamine and other chemical mediators. 1 , 5 , 6 …”

“Next top” mouse models advancing CTCL research

“…The NOD SCID mouse model, formally designated as the NOD. CB17-Prkdc scid strain, is valuable in CTCL research as recipient mice due to its lack of mature T and B cells, making it suitable not only for studying pruritus—a hallmark symptom of CTCL ( Prochazka et al, 1992 ) —but also for investigating tumor growth and early symptoms ( Chen et al, 2023 ; Furutani et al, 2023 ). Employing the NOD SCID mice for the CTCL model, LW-213 was found to significantly inhibit CTCL tumor growth and enhance survival rates ( Yu et al, 2021 ).…”