Characterization of a mouse model of sickle cell trait: parallels to human trait and a novel finding of cutaneous sensitization

Abstract

Sickle cell trait (SCT) has classically been categorized as a benign condition except in rare cases or upon exposure to severe physical conditions. However, several lines of evidence indicate that individuals with SCT are not always asymptomatic, and additional physiological changes and risks may remain unexplored. Here, we utilized mice harbouring one copy of normal human β globin and one copy of sickle human β globin as a model of SCT, to assess haematological, histopathological and somatosensory outcomes. We observed that SCT mice displayed renal and hepatic vascular congestion after exposure to hypoxia. Further, we observed that SCT mice displayed increased cold aversion as well as mechanical and heat sensitivity, though to a lesser degree than homozygous sickle cell disease mice. Notably, mechanical hypersensitivity increased following hypoxia and reoxygenation. Overall our findings suggest that SCT is not entirely benign, and further assessment of pain and cutaneous sensitization is warranted both in animal models and in clinical populations.

Chemokine (c-c motif) receptor 2 mediates mechanical and cold hypersensitivity in sickle cell disease mice

“…It should be noted that unlike in the plantar cold testing, the less severe model of SCD ( i.e ., Townes AS) exhibited mechanical withdrawal thresholds that were statistically similar to those observed in the severe Berk SS model of SCD. Previously published data from our lab demonstrate an intermediate phenotype for AS mice when compared to SS mice of the same genetic background (Townes SS) [64]. The highly variable nature of von Frey testing, sample size, and number of post hoc analyses, may contribute to the observed similarities between genotypes ( i.e ., Townes AS and Berk SS) in these experiments.…”

“…Instead, these animals contain one copy of normal adult human β globin and one copy of adult human sickle β globin, in addition to normal human α globin within the mouse globin locus. As such, Townes AS mice model sickle cell trait in humans, and portray a mild phenotype of several components of SCD pathology [64]. Since Berk and Townes mice both contain considerable genetic background from C57BL/6 and 129 mice, B6;129 hybrid animals were used as a shared control.…”

Neuronal transient receptor potential (TRP) channels and noxious sensory detection in sickle cell disease

“…18 Interestingly, heat pain hypersensitivity is not further exacerbated during episodes of acute pain, which is consistent with patient use of innocuous heat as analgesia during these pain events 30 . Like patients, the Berk 19,[31][32][33] and Townes 14,34 transgenic animal models of severe SCD and less severe models of sickle cell trait (SCT; Berk AS) 35 all exhibit heat hyperalgesia during steady state health as measured by decreased paw withdrawal latencies to heat stimulation. In vivo recordings of C fibers from Berk mice further demonstrate heat hypersensitivity on the neuronal level; despite having similar heat thresholds, C fibers from naïve Berk mice fire more action potentials than C fibers from naïve control mice over the course of a warm ramp stimulation (36°C to 50°C) 8 .…”

“…In our initial 2011 report and most recent 2018 study, we describe a role for TRPV1 in the mechanical hypersensitivity observed in SCD mice 7,19 . Many labs have documented chronic mechanical allodynia in transgenic SCD and SCT mouse models as assessed by von Frey filament responsiveness 7,9,10,14,15,19,31,32,34,47,77,78 . Like heat, sensitivity to this modality is further amplified following VOC in both mouse models and SCD patients 14,19,30,32,47 .…”

“…Transgenic mouse models of SCD and SCT also exhibit increased cold sensitivity. SCD/T mice have shorter paw withdrawal latencies to cold stimulation than control mice and spend significantly less time in cold environments during two-temperature choice assays 7,14,15,19,32,33,77 , a behavior that is further exacerbated following VOC 14,15,32 . Similar temperature sensitivity is noted on the cellular level.…”