Figure 7.

LPC and miR-146a are elevated in mice or patients with PBC with cholestatic itch and induced itch in nonhuman primates. (A) ANIT treatment increased LPC levels in serum and skin. **P < .01 and ***P < .001 vs WT-control, 2-tailed t test (n = 5–8 mice/group). (B) ANIT treatment increased miR-146a in serum, which was attenuated in keratinocyte-Trpv4 cKO mice. *P < .05 vs WT control, and #P < .05 vs keratinocyte-Trpv4 cKO mice, 1-way analysis of variance with Tukey’s post hoc test (n = 8–11 mice/group). (C) ANIT-induced cholestatic itch was significantly attenuated in keratinocyte-Trpv4 cKO mice. *P < .05, **P < .01, ***P < .001 vs WT control; #P < .05 vs #P < .05 vs keratinocyte-Trpv4 cKO mice, 2-way analysis of variance with Tukey’s post hoc test (n = 6 mice/group). (D) All detected LPC species, except for LPC(20:4), were significantly elevated in sera of patients with PBC with itch (n = 27) vs without itch (n = 21), *P < .05 and **P < .01, 2-tailed t test. (E) When all detected LPC species from individual patients were aggregated, there was a significant correlation of total LPC concentration with the itch intensity. Pearson’s correlation coefficient, R = 0.4314; P =.0029. (F) A significant increase in abundance of miR-146a was detected in sera of patients with PBC with itch (n = 10) vs without itch (n = 12), **P < .01, 2-tailed t test. (G) Note a significant correlation of miR-146a level with the itch intensity. Pearson’s correlation coefficient, R = 0.4536; P = .034. (H) LPC or miR146a induced scratching behavior in rhesus monkeys in a dose-dependent manner. Histamine was used as positive control. i.d., intradermal. ***P < .001, #P < .05, ##P < .01, and $ $ $P < .001 vs normal saline (NS), repeated measures using a linear mixed model (n = 9 monkeys/group). The error bars indicate the standard error of the mean.