Fig 2: Effect of repeated SD on IL-6 and CX3CL1 levels in the striatum and PFC. Bars represent mean pro-inflammatory cytokine IL-6 (in pg/mg) and chemokine CX3CL1 levels (in ng/mg) in the striatum (a and b) and PFC (c and d) and vertical lines ± SEM. Mice were divided into Control (n = 12); Resilient (n = 14) and Susceptible (n = 16). Defeated mice were characterized as resilient or susceptible depending on their SWR. *p < 0.05, **p < 0.01, ***p < 0.001 significant difference with respect to the control; ++ p < 0.01 significant difference with respect to resilient mice.

Fig 3: Related to Figures 6 and 7(A) Relative tumor growth and (B) tumor weights of CAL51 (PIK3CA MUT)-derived xenografts stably expressing control shGFP or two independent shRNAs targeting cPLA2 (cPLA2-sh1 and cPLA2-sh5) in mice fed a balanced omega3:omega6 diet. (C) Relative tumor growth and (D) tumor weights of Hs578T (PIK3CA WT)-derived xenografts stably expressing control shGFP or cPLA2-sh1 or cPLA2-sh5 in mice fed a balanced omega3:omega6 diet. AA levels measured by REIMS in (E) PIK3CA MUT (CAL51) and (F) PIK3CA WT (Hs578T) snap frozen excised tumors. AA intensities are reported as scaled values to the appropriate shGFP-fat free diet control. Quantification of CCL5 from excised tumors derived from (G) PDX and (H) cell line-derived xenograft studies. Quantification of CX3CL1 from excised tumors derived from (I) PDX and (J) cell line-derived xenograft studies. Concentrations of chemokines in (G-J) were determined from whole tumor lysates using ELISA, and normalized to protein content. (K) Representative immunohistochemical staining of the activated NK cell marker NKp46 in BR1282 (PIK3CA MUT) and BR1458 (PIK3CA WT) PDX tumors. (L) and (M) Quantification of positively immunostained areas from (K). (N) Representative immunohistochemical staining of NKp46 in shGFP, cPLA2-sh1 and cPLA2-sh5 expressing CAL51 (PIK3CA MUT) and Hs578T (PIK3CA WT)-derived xenograft tumors under fat free or ‘Western’ diets. (O) and (P) Quantification of positively immunostained areas from (N). Data in (A), (C), and (E) to (J) are presented as the mean ± SEM of n = 3–5 mice for cell line xenograft or n = 7–8 mice for PDX studies. n.s., not significant; *p < 0.05; **p < 0.01; ***p < 0.001; P values in (A) and (C) were calculated using two-way ANOVA, and one-way ANOVA followed by unpaired, two tailed Student’s t test with Bonferroni correction was used in (B), (D), (E), (F), (G), (H), (I), (J), (L), (M), (O), (P).

Fig 4: Cardiomyocyte-specific ADAM10/CX3CL1 signaling regulates neutrophil migration.a Immunofluorescence images and b quantification of CX3CL1, cardiac Troponin T (cTnT, cardiomyocytes, CM) and CD31 (endothelial cells, EC) stained heart tissue sections of sham-operated (Sham) and LAD-ligated (MI) mice 14 days after surgery. Nuclei are stained with DAPI. Representative images are shown. Scale bar, 20 µm. n = 4 per group, mean ± SEM, ns not significant, two-tailed Mann–Whitney test with Dunn’s posttest. c Co-immunoprecipitation of endogenous ADAM10 (A10) and CX3CL1 from whole-cell lysates of HL-1 cells. Representative western blots are shown (n = 4). IgG, immunoglobulin G as a control. WCL, whole-cell lysate. d Western blot analysis of CX3CL1 and e quantification of CX3CL1 expression (n = 6 per group, mean ± SEM, ns not significant, **P < 0.01, ***P < 0.001, one-way ANOVA with Tukey’s posttest) as well as f ectodomain shedding (CX3CL1 levels in supernatant) in normoxic as well as GI254023X (A10i) and DMSO treated hypoxic (1% O2) mouse cardiomyocytes (HL-1) (n = 3 per group, mean ± SEM, ns not significant, **P < 0.01, Kruskal–Wallis test with Dunn’s posttest, exact P-values are provided in the Source Data file). g Treatment scheme. HL-1 cells were cultured for 3 h under normoxic or hypoxic conditions in parallel to A10i or DMSO treatment in combination with unspecific control siRNA (siC) or CX3CL1 depletion (siCX3CL1). Supernatants were used in the lower chamber and 3 × 105 freshly isolated mouse bone marrow derived neutrophils or macrophages were seeded in the upper chamber of transwell plates (8 µm pore size) to determine migration capacity. The scheme was created using Servier Medical Art (available online: http://smart.servier.com). h Western blot analysis and i quantification of CX3CL1 expression in HL-1 cells treated for 48 h with unspecific control siRNA (siC) or CX3CL1-specific siRNA (siCX3#1 and siCX3#2). Representative western blots (n = 3 per group, mean ± SEM, **P < 0.01, Kruskal–Wallis test with Dunn’s posttest) are shown. Exact P-values: siC vs. siCX3#1, 0.0043. siC vs. siCX3#2, 0.005. Transwell migration assays of bone marrow derived j neutrophils and k macrophages using the supernatants of HL-1 cells that were cultured under hypoxic conditions in parallel to A10i or DMSO treatment in combination with unspecific control siRNA (siC) or CX3CL1 depletion (siCX3#1 and CX3#2) as chemoattractant (n = 3 per group, mean ± SEM, ns not significant, **P < 0.01, Kruskal–Wallis test with Dunn’s posttest). Source data and exact P-values are provided in the Source Data file.

Fig 5: Cardiomyocyte-specific ADAM10 KO improves post-MI cardiac function.a–c Echocardiographic assessment of fractional area shortening, ejection fraction and left ventricular end-systolic interior diameter in 8-week-old ADAM10fl/fl (WT) and (aMHC-Cre) ADAM10 KO mice under a basal conditions (WT, n = 7, KO, n = 8, mean ± SEM, ns not significant) as well as b 3 days (WT, n = 8, KO, n = 9, mean ± SEM, ns not significant, *P < 0.05, two-tailed t test) and c 14 days after myocardial infarction (WT, n = 6, KO, n = 9, mean ± SEM, ns not significant, *P < 0.05, two-tailed t test, exact P-values are provided in the Source Data file). d Representative end-systolic B-mode and M-mode echocardiograms of ADAM10 WT and ADAM10 KO mice 14 days after myocardial infarction. e Western blot analysis and f quantification of ADAM10, CX3CL1 and IL-1ß expression in heart tissue lysates of ADAM10 WT and ADAM10 KO mice 3 days after myocardial infarction (n = 6, mean ± SEM, ns not significant, *P < 0.05, **P < 0.01, two-tailed t test). Exact P-values: ADAM10, 0.0159. CX3CL1, 0.0084. IL-1ß, 0.0317. g Analysis of leukocyte counts in blood samples of ADAM10 WT (n = 8) and ADAM10 KO (n = 7) mice (mean ± SEM, ns not significant, *P < 0.05, two-tailed t test). Exact P-values: Neutrophils, 0.0404. Eosinophils, 0.7886. Monocytes, 0.3373. Lymphocytes, 0.751. h Analysis of leukocyte counts in the infarcted area/ infarct border zone of ADAM10 WT (n = 8) and ADAM10 KO (n = 7) mice (mean ± SEM, ns not significant, *P < 0.05, two-tailed two-tailed t test). Exact P-values: Neutrophils, 0.0214. Eosinophils, 0.176. Monocytes, 0.639. Macrophages, 0.6064. Source data are provided as a Source Data file.