Fig. 1: Acute thymic damage triggers the cleavage of Cas-1 and the activation of IL-18, which suppresses thymus regeneration.
From: Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration
a,b, Female 1- to 2-month-old C57/BL6 mice were administered SL-TBI (550 cGy), dexamethasone (intraperitoneal (i.p.) injection, 20 mg kg−1), cyclophosphamide (i.p., 200 mg kg−1) or LPS (i.p., 1.5 mg kg−1). a, Thymus cellularity (black) and cl-Cas-1 expression (red) were measured using fluorescently conjugated FAM-YVAD-FMK (a fluorescent probe that irreversibly binds and labels cl-Cas-1) in mice killed at baseline (n = 15), day 0.5 (n = 7), day 1 (n = 8), day 3 (n = 8), day 5 (n = 4) and day 7 (n = 4) after treatment; all statistics are compared to day 0. b, Amount of active IL-1β and active IL-18 in the thymus, measured by ELISA at the indicated time points after SL-TBI (IL-18: day 0, n = 9; day 0.5, n = 6; day 1, n = 6; day 3, n = 5; IL-1β: day 0, n = 4; day 0.5, n = 3; day 1, n = 3; day 3, n = 3), dexamethasone (i.p., 20 mg kg−1) (IL-18: day 0, n = 9; day 0.5, n = 3; day 1, n = 7; day 3, n = 6; IL-1β: day 0, n = 4; day 0.5, n = 3; day 1, n = 3; day 3, n = 3), cyclophosphamide (i.p., 200 mg kg−1) (IL-18: day 0, n = 5; day 1, n = 4; day 3, n = 4; IL-1β: day 0, n = 4; day 0.5, n = 3; day 1, n = 2; day 3, n = 3) or LPS (i.p., 1.5 mg kg−1) (IL-18: day 0, n = 9; day 0.5, n = 6; day 1, n = 6; day 3, n = 6; IL-1β: day 0, n = 3; day 0.5, n = 4; day 1, n = 3; day 3, n = 3); all statistics are compared to day 0. c, Amount of active IL-18 measured by ELISA in thymuses of female 1- to 2-month-old Cas1Δ10 mice on day 0 (n = 7) and day 1 (n = 8) after SL-TBI. d, Amount of IL-18BP in thymuses of 1- to 2-month-old C57/BL6 WT mice on days 0, 1 and 3 after SL-TBI (n = 3 per group). e, Ratio of active IL-18 to IL-18BP averaged on day 0 (n = 9), day 1 (n = 6) and day 3 (n = 5) after SL-TBI, representing the amount of free active IL-18. f, Female 1- to 2-month-old C57/BL6 WT (n = 18), Il1r1−/− (n = 3), Il18−/− (n = 7) and Il18r1−/− (n = 8) mice were exposed to SL-TBI, and thymus cellularity was measured 7 days later. g, Female 1- to 2-month-old C57/BL6 WT (n = 7) or Cas1Δ10 (n = 8) mice were exposed to SL-TBI, and thymus cellularity was measured on day 7. h, Female 1- to 2-month-old C57/BL6 WT mice were exposed to SL-TBI and then administered PBS vehicle (n = 12) or rIL-18 (n = 10) on day 3 (subcutaneous (s.c.) injection, 2.5 mg kg−1); thymuses were isolated on day 7. i, Female 1- to 2-month-old C57BL/6 mice were lethally irradiated and transplanted (intravenous (i.v.) injection) with 5 × 106 CD45.1+ WT bone marrow hematopoietic cells. Recipient mice were treated with 200 μg of anti-IL-18 mAb (n = 10) or equal-volume control (PBS) (n = 11), and thymus cellularity was measured on day 50 following transplant. Graphs represent mean ± s.e.m.; each dot represents an individual biological replicate; NS, not significant. Statistics were generated for a, b and d–f using one-way analysis of variance (ANOVA) with Dunnet’s correction for multiple comparisons and for c and g–i using unpaired two-tailed t tests. Panel a icons created with BioRender.com.
