Background & Aims
Chemotherapy-induced peripheral neuropathy (CIPN) affects between 19 – 85% of those treated, depending on the chemotherapeutic compound and dose used. Typically, CIPN develops in the feet and hands first, manifesting as numbness, tingling, impaired vibration and altered touch sensations. Painful sensations including non-evoked burning, shooting or electric shock-like pain as well as mechanical or thermal allodynia or hyperalgesia frequently occur. CIPN is often a limiting factor for chemotherapy, leading to dose reduction, or even cessation, resulting in suboptimal cancer treatment.
Individuals of African ancestry are more likely to experience CIPN. We studied acute and chemotherapy related pain outcomes in mice with abolition of atypical chemokine receptor 1 (ACKR1) in erythroid cells, a phenotype present in over two-thirds of individuals of African ancestry, to determine if this mutation contributes to altered acute pain thresholds and/or exacerbated inflammatory pain and CIPN.
Methods
ACKR1 erythroid cell conditional knock-out (ACKR1 cKO) mice were generated. To measure acute pain thresholds in the hind paw of adult ACKR1 cKO mice and littermate controls, we performed up-down von Frey as a measure of mechanical sensitivity, the Hargreaves assay to measure heat sensitivity, and the cold plantar assay to measure sensitivity to cold. To study inflammatory pain, we injected 20 µl of Complete freund’s adjuvant (CFA) into the plantar surface of the hind paw. Mechanical and thermal heat sensitivity was then tested (as described above) for a duration of 14 days after CFA injection.
To investigate the role of erythroid cell ACKR1 in CIPN, we injected adult ACKR1 cKO mice and littermate control mice intraperitoneally with 8mg/kg of the chemotherapeutic paclitaxel (PTX) every other day for a total of four injections, to induce CIPN. To monitor behavioural outcomes we used up-down von Frey and the cold plantar assay, for a duration of 28 days after the first PTX injection.
Results
We observe a mild reduction in sensitivity to acute heat stimuli in male ACKR1 cKO mice compared to littermate controls. However, in the presence of inflammation, ACKR1 cKO male mice are significantly more sensitized to heat than littermates. In addition, our data shows a significant increase in sensitivity to mechanical and cold stimuli in ACKR1 cKO mice following induction of CIPN. This is related to changes in paw vasculature and immune cell trafficking to peripheral tissues.
Conclusions
Individuals of African ancestry are more likely to experience CIPN. Our data in a mouse model suggest that the biological basis of this phenomenon is due to the prevalent genetic mutation of ACKR1 on erythroid cells.
References
Duchene, J., Novitzky-Basso, I., Thiriot, A. et al. Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis. Nat Immunol 18, 753–761 (2017). https://doi.org/10.1038/ni.3763