Fig 2: IL18 is dispensable for the generation of IL18Ra+ progenitors. (A, B) Percentage and numbers of BM progenitors and ILC2 in Il18+/+ and Il18-/- mice. (C) Percentage of IL-18Ra+ cells in each population from panel A (presented in dark blue and dark red, respectively) and mean fluorescence intensity of IL-18Ra (presented in light blue and light red, respectively) in Il18+/+ and Il18-/- mice. (D, E) Numbers of B cells, CD4+ T cells, CD8+ T cells, NK cells, and ILC1 cells in spleen and liver of Il18+/+ and Il18-/- mice. (F) Number of total T1ST2+ ILC2 and activated T1ST2+KLRG1+ ILC2 in the lung of Il18+/+ and Il18-/- mice. (G–I) Percentage of ILC2 and ILC3 in mesenteric lymph nodes, small intestine, and large intestine of Il18+/+ and Il18-/- mice. Data are representative of three or more independent experiments with three or more mice in each group. The data are presented as mean ± SEM.

Fig 3: ILC development in the absence of IL18Ra signaling. (A) Numbers of BM progenitors and ILC2 from Il18r1+/+ and Il18r1-/- mice. (B) Representative FACS plot showing the expression of PD-1 in Flt3-aLP from Il18r1+/+ and Il18r1-/- BM. (C) Percentage of PD-1+ in aLP from Il18r1+/+ and Il18r1-/- mice. (D, E) Numbers of B cells, CD4+ T cells, CD8+ T cells, NK cells, and ILC1s in the spleen and liver from Il18r1+/+ and Il18r1-/- mice. (F) Number of total T1ST2+ ILC2 and activated T1ST2+KLRG1+ ILC2 in the lung of Il18r1+/+ and Il18r1-/- mice. (G–I) Percentage of ILC2 and ILC3 in mesenteric lymph nodes, small intestine, and large intestine from I Il18r1+/+ and Il18r1-/- mice. (J) Cell expansion of Il18r1+/+ and Il18r1-/- BM CLP (50~200 cells) and aLP (100~300 cells) after culture on OP9-DL1 with 20 ng/ml SCF and 20 ng/ml IL-7 for 14 days. (K) Reconstitution of lymphoid cell compartment in Rag2-/-Il2r?-/- mice adoptively transferred with Il18r1+/+ and Il18r1-/- BM CLPs. Data are representative of two independent experiments with three mice in each group. The data are presented as mean ± SEM, analyzed by two-tailed Student’s t-test. “nc” = negative control, meaning no added IL-18 in culture system. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001.

Fig 4: Attenuation of IL‐18/glypican 3 (GPC3) axis in livers of GSDMD −/− mice compared with controls after surgery. (A) The mRNA levels of IL‐18 and GPC3 were measured by quantitative PCR (GSDMD +/+ , n = 3–5/group; GSDMD +/− , n = 0–3/group; GSDMD −/− , n = 3–8/group). (B) Western blotting for GPC3 in remnant livers of GSDMD +/+or‐ and GSDMD −/− mice at various time points after 70%PH. GAPDH served as loading control. (C) Serum IL‐18 was detected by enzyme‐linked immunosorbent assay (ELISA; GSDMD +/+ , n = 3/group; GSDMD +/− , n = 1/group; GSDMD −/− , n = 4/group). (D) Primary mouse hepatocytes were treated with indicated concentration of recombinant IL‐18 for 48 hours, and the mRNA and protein levels of GPC3 were analyzed by quantitative PCR and western blotting. The sham group were collected at 48 hours after sham surgery. Data are presented as mean ± SD; *p < 0.05, **p < 0.01

Fig 5: Pharmacological inhibition of GSDMD by DSF‐ameliorated liver injury and regeneration after 70%PH. (A) Evaluating the degree of liver regeneration and liver injury in oil‐treated and DSF‐treated mice by measuring liver/body ratio and serum ALT. (B,C) Representative pictures and quantification for BrdU‐positive and p‐H3‐positive hepatocytes in liver slides of oil‐treated and DSF‐treated mice at 48 hours and 72 hours after surgery (n = 3–4/group). (D) Serum IL‐1β and IL‐18 were detected by ELISA (n = 4/group). (E) The protein levels of PCNA, activin A, and activation of smad2/3, IL‐1β, and IL‐18 were examined by western blotting. GAPDH served as loading controls. Graphs represent mean ± SD of BrdU+ and p‐H3+ hepatocytes/HFP. Data are presented as mean ± SD; *p < 0.05, **p < 0.01