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. Author manuscript; available in PMC: 2018 Feb 6.

Published in final edited form as: Inflammation. 2017 Feb;40(1):21–41. doi: 10.1007/s10753-016-0449-5

Two groups of sex-matched 12-month VCP^R155H/+ heterozygotes mice (n = 8 mice per group) received oral gavage of 30-mg/kg of MCC950 inhibitor for 4 consecutive weeks. Untreated age- and sex-matched VCP^R155H/+ heterozygotes mice were used as controls. (A) The hematoxylin and eosin sections showing cell infiltrates in muscle of treated vs. Untreated VCP^R155H/+ heterozygote mice (Magnification at 40× and 63×). As depicted, yellow dotted lines show fibrosis, central nucleation indicating regeneration, and degenerating fibers, and yellow arrows point to persistent neutrophils, macrophages and necrotic myocytes. Quadriceps, brains, and bones were harvested 4 weeks later from untreated and treated mice and stained with mAbs specific to markers of NLRP3 inflammasome activation (NLRP3, Caspase 1, and IL-1β and mAbs specific to markers of pathology TDP-43 and p62/SQSTM1) as performed in Figs. 2 and 5. (B) Representative FACS histograms of the levels of markers of inflammasome activation and of pathology (NLRP3, Caspase 1, IL-1β, TDP-43, and P62/SQSTM1) detected by flow cytometry from one treated (black line) and untreated (white line) VCP^R155H/+ heterozygote mice. (C) The bar graphs represent the means and SD of the mean fluorescent intensity (MFI) each marker (NLRP3, Caspase 1, IL-1β, TDP-43, and P62/SQSTM1) from a group of 8 treated and 8 untreated VCP^R155H/+ heterozygotes mice. (*) Indicates P < 0.05 when comparing treated and untreated mice using ANOVA test. (D) Percentages (left graph) and number (right graph) of F4/80⁽⁺⁾IL-1β⁽⁺⁾ macrophages determined in the muscle from treated versus untreated VCP^R155H/+ heterozygote mice. (E) Percentages (left graph) and numbers (right graph) of IL-1β⁽⁺⁾Ly6C⁽⁺⁾ macrophages determined in the muscle from treated versus untreated VCP^R155H/+ heterozygote mice. (F and G) Body size/shape of treated versus untreated VCP^R155H/+ heterozygote mice, (H) ROC curve showing weight loss (red line = treated; blue line = untreated), and (I and J) muscle mass loss of fore limb quadriceps observed in untreated versus treated VCP^R155H/+ heterozygote mice.

Two groups of sex-matched 12-month VCP^R155H/+ heterozygotes mice (n = 8 mice per group) received oral gavage of 30-mg/kg of MCC950 inhibitor for 4 consecutive weeks. Untreated age- and sex-matched VCP^R155H/+ heterozygotes mice were used as controls. (A) The hematoxylin and eosin sections showing cell infiltrates in muscle of treated vs. Untreated VCP^R155H/+ heterozygote mice (Magnification at 40× and 63×). As depicted, yellow dotted lines show fibrosis, central nucleation indicating regeneration, and degenerating fibers, and yellow arrows point to persistent neutrophils, macrophages and necrotic myocytes. Quadriceps, brains, and bones were harvested 4 weeks later from untreated and treated mice and stained with mAbs specific to markers of NLRP3 inflammasome activation (NLRP3, Caspase 1, and IL-1β and mAbs specific to markers of pathology TDP-43 and p62/SQSTM1) as performed in Figs. 2 and 5. (B) Representative FACS histograms of the levels of markers of inflammasome activation and of pathology (NLRP3, Caspase 1, IL-1β, TDP-43, and P62/SQSTM1) detected by flow cytometry from one treated (black line) and untreated (white line) VCP^R155H/+ heterozygote mice. (C) The bar graphs represent the means and SD of the mean fluorescent intensity (MFI) each marker (NLRP3, Caspase 1, IL-1β, TDP-43, and P62/SQSTM1) from a group of 8 treated and 8 untreated VCP^R155H/+ heterozygotes mice. (*) Indicates P < 0.05 when comparing treated and untreated mice using ANOVA test. (D) Percentages (left graph) and number (right graph) of F4/80⁽⁺⁾IL-1β⁽⁺⁾ macrophages determined in the muscle from treated versus untreated VCP^R155H/+ heterozygote mice. (E) Percentages (left graph) and numbers (right graph) of IL-1β⁽⁺⁾Ly6C⁽⁺⁾ macrophages determined in the muscle from treated versus untreated VCP^R155H/+ heterozygote mice. (F and G) Body size/shape of treated versus untreated VCP^R155H/+ heterozygote mice, (H) ROC curve showing weight loss (red line = treated; blue line = untreated), and (I and J) muscle mass loss of fore limb quadriceps observed in untreated versus treated VCP^R155H/+ heterozygote mice.