by Ganesh V. Halade, Paul C. Norris, Vasundhara Kain, Charles N

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Splenic leukocytes define the resolution of inflammation in heart failure by Ganesh V. Halade, Paul C. Norris, Vasundhara Kain, Charles N. Serhan, and Kevin A. Ingle Sci. Signal. Volume 11(520):eaao1818 March 6, 2018 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Infarcted LV healing is associated with expression of different LOX isoforms in mice after MI. Infarcted LV healing is associated with expression of different LOX isoforms in mice after MI. (A) Study design. (B) Fractional shortening (%) measured from the long axis. n = 6 mice per group per day. (C) Post-MI percentage of LV infarcted area compared to naïve controls with no infarct. n = 6 mice per group per day. (D) Representative echocardiographic long-axis B-mode images of naïve control and d1 and d5 post-MI mice. (E and F) Representative images from horizontal sections of LV mid-cavity stained with (E) hematoxylin and eosin (H&E) and (F) picrosirius red (PSR). Scale bars, 50 μm. n = 6 mice per group per day. (G to I) Expression analysis of (G) ALOX15, (H) ALOX12, (I) and ALOX5 in infarcted LV or spleen from naïve control mice or at the indicated time points after MI. Expression was normalized to Hprt-1. n = 6 mice per group per day. (J and K) Expression analysis of (J) COX-2 and (K) COX-1 in infarcted LV from naïve control mice or at the indicated time points after MI. LOX and COX gene expression was normalized to Hprt-1. n = 6 mice per group per day. *P < 0.05 compared to no-MI naïve control and $P < 0.05 compared to spleen at respective day time point using one-way analysis of variance (ANOVA). Ganesh V. Halade et al., Sci. Signal. 2018;11:eaao1818 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

SPM biosynthesis peaked in the infarcted LV and was reduced in spleen after MI within 24 hours. SPM biosynthesis peaked in the infarcted LV and was reduced in spleen after MI within 24 hours. (A) Pie chart representing the distribution of SPMs and DHA, EPA, and AA in infarcted LV from naïve control mice or at the indicated time points after MI. n = 4 mice per group per day. (B) Pie chart representing the distribution of SPMs and DHA, EPA, and AA metabolome in spleen from naïve control mice or at the indicated time points after MI. Percentage of mean values for each of the lipid mediators identified are presented in the pie chart. n = 4 mice per group per day. Quantification and values are pg/50 mg of LV tissue from apex to base and pg/50 mg of spleen tissue. The detection limit was ~1 pg. Ganesh V. Halade et al., Sci. Signal. 2018;11:eaao1818 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Infarcted LV macrophage activation is inversely proportional to lipoxin kinetics in the spleen within 24 hours after MI. Infarcted LV macrophage activation is inversely proportional to lipoxin kinetics in the spleen within 24 hours after MI. (A) Representative flow cytometry [fluorescence-activated cell sorting (FACS)] dot plots showing the macrophage population (CD11b+/F4/80+) in spleen (left) and LV mononuclear cells (right) in no-MI naïve control and at d1 and d5 after MI. (B) Line graph showing the percentage of the F4/80+ population in spleen and LV mononuclear cells at d0 and at d1 and d5 after MI. n = 4 mice per group per day. (C) Line graph showing the kinetics of LTB4 in LV and spleen in no-MI control and at d1 and d5 after MI. n = 4 mice per group per day. (D) Line graph showing the kinetics of LXB4 in no-MI control and at d1 and d5 after MI in LV and spleen. n = 4 mice per group per day. (E) Line graph showing the kinetics of AT-LXA4 in LV and spleen in no-MI control and at d1 and d5 after MI. Results are means ± SEM. Quantification and values in (C) to (E) are pg/50 mg of spleen or infarcted LV tissue from apex to base. The detection limit was ~1 pg. *P < 0.05 compared to no-MI naïve control and $P < 0.05 compared to spleen at respective day time point using one-way ANOVA. Ganesh V. Halade et al., Sci. Signal. 2018;11:eaao1818 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Infarcted LV contains activated leukocytes, and SPM biosynthesis is increased in spleen and infarcted myocardium after MI. Infarcted LV contains activated leukocytes, and SPM biosynthesis is increased in spleen and infarcted myocardium after MI. (A) Representative flow cytometry (FACS) dot plots showing the neutrophil population (CD11b+/Ly6G+) in spleen (left) and LV mononuclear cells (right) in no-MI naïve control and at d1 and d5 after MI. (B) Line graph showing the percentage of the Ly6G+ population in spleen and LV mononuclear cells at d0, d1, and d5 after MI. n = 4 mice per group per day. (C) Line graph showing the kinetics of RvD1 in LV and spleen in no-MI control and at d1 and d5 after MI. n = 4 mice per group per day. (D) Line graph showing the kinetics of RvD5 in LV and spleen at d1 and d5 after MI compared to spleen and LV d0 naïve controls. n = 4 mice per group per day. Quantification and values in (C) and (D) are pg/50 mg of spleen or infarcted LV tissue from apex to base. *P < 0.05 compared to no-MI naïve control and $P < 0.05 compared to spleen at respective day time point using one-way ANOVA. Ganesh V. Halade et al., Sci. Signal. 2018;11:eaao1818 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Splenic monocyte/macrophage subsets (F4/80+/Ly6Clow) that increase in the infarcted LV within 24 hours are associated with biosynthesis of MaR1. Splenic monocyte/macrophage subsets (F4/80+/Ly6Clow) that increase in the infarcted LV within 24 hours are associated with biosynthesis of MaR1. (A) Representative flow cytometry (FACS) dot plots showing macrophage population (F4/80+/Ly6C+) in spleen (left) and LV mononuclear cells (right) in no-MI naive control and at d1 and d5 after MI. (B) Line graph showing the percentage of the Ly6Chigh population in spleen and LV mononuclear cells at d0, d1, and d5 after MI. n = 4 mice per group per day. (C) Line graph showing the percentage of the Ly6Clow population in spleen and LV mononuclear cells in d0 naïve controls and d1 and d5 post-MI mice. n = 4 mice per group per day. (D) Line graph showing the kinetics of MaR1 in LV and spleen in no-MI control and at d1 and d5 after MI. n = 4 mice per group per day. Results are means ± SEM. Quantification and values of analytes are pg/50 mg of spleen or LV infarct tissue from apex to base. The detection limit was ~1 pg. *P < 0.05 compared to no-MI naïve control and $P < 0.05 compared to spleen at respective day time point using one-way ANOVA. Ganesh V. Halade et al., Sci. Signal. 2018;11:eaao1818 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Leukocyte activation in infarcted LV and spleen is associated with overlapping inflammatory and resolving phenotypes. Leukocyte activation in infarcted LV and spleen is associated with overlapping inflammatory and resolving phenotypes. (A) Representative histogram overlay of inflammatory and resolving leukocytes in LV. n = 4 mice per group per day. (B) Representative histogram overlay of inflammatory and resolving leukocytes in spleen. n = 4 mice per group per day. (C to F) Line graphs showing the kinetics of the Ly6G−/CD206+ (C), Ly6G+/CD206+ (D), Ly6Chigh/CD206+ (E), and Ly6Clow/CD206+ (F) populations in LV and spleen. Results are expressed as means ± SEM. n = 4 mice per group per day. *P < 0.05 compared to no-MI naïve control and $P < 0.05 compared to spleen at respective day time point using one-way ANOVA. Mo, monocytes; Neu, neutrophils; M∅, macrophages; N2, resolving neutrophils; M2, resolving macrophages. Ganesh V. Halade et al., Sci. Signal. 2018;11:eaao1818 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Macrophage depletion reduced LOX expression and thereby SPMs after MI. Macrophage depletion reduced LOX expression and thereby SPMs after MI. (A) Scheme illustrating the experimental design for CLD treatment in MI model. (B) Representative flow cytometry (FACS) dot plots showing the monocyte population (CD11b+CD45+) mononuclear cells in spleen (top) and infarcted LV (bottom) in MI control and CLD-injected mice. (C) Bar graph representing CD11b+ cells. (D) FACS dot plots showing the mononuclear macrophage population (CD11b+F4/80+) in spleen (top) and infarcted LV (bottom) in MI control and CLD-injected mice. (E) Bar graph representing F4/80+ cells (open bar MI control and filled bar MI + CLD). n = 4 mice per group. (F to H) Gene expression analysis of ALOX15 (F), ALOX12 (G), and ALOX5 (H) in spleen and infarcted LV after MI in CLD-injected mice. Gene expression was normalized to Hprt-1. n = 4 mice per group. (I and J) Gene expression analysis of COX-2 (I) and COX-1 (J) in spleen and infarcted LV after MI in CLD-injected mice. Gene expression was normalized to Hprt-1. n = 4 mice per group. *P < 0.05 compared to MI control and $P < 0.05 compared to spleen using one-way ANOVA. (K to P) Measurement of LXA4 (K), AT-LXA4 (L), RvD4 (M), LTB4 (N), LXB4 (O), and PGE2 (P) in spleen (open bar) and infarcted LV (filled bar) at d1 post-MI after CLD-mediated macrophage depletion. Results are mean ± SEM values. n = 3 mice per group. Quantified values of analytes are pg/50 mg of spleen or LV infarct tissue from apex to base. The detection limit was ~1 pg. Ganesh V. Halade et al., Sci. Signal. 2018;11:eaao1818 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Activated cytokine and chemokine signal is amplified early in spleen than LV in post-MI resolution of inflammation. Activated cytokine and chemokine signal is amplified early in spleen than LV in post-MI resolution of inflammation. (A to F) mRNA expression of IL-1b (A), Ccl2 (B), C3 (C), IL-10 (D), CxCL10 (E), and Ccr6 (F) in spleen or infarcted LV from naïve control mice or at the indicated time points after MI. Results are expressed as means ± SEM. n = 4 mice per group. *P < 0.05 compared to no-MI naïve control and $P < 0.05 compared to spleen at respective day time point using one-way ANOVA. (G) Model showing that leukocytes in the spleen generated SPMs through LOX isoforms that advance the resolution of inflammation and healing in the LV after MI. CLD-mediated macrophage depletion reduced the expression of LOX isoforms and generation of SPMs, thereby triggering nonresolving inflammation that can lead to HF. (H) Model showing that after MI, LOXs are preferentially activated in the infarcted LV to generate SPMs that promote cardiac repair. Ganesh V. Halade et al., Sci. Signal. 2018;11:eaao1818 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works