MedicinesHost Response with Novel Nanoproresolving Inflammation in Mice: Reprogramming the Aging Delays Resolution of Acute

Aging is associated with an overt inflammatory phenotype and physiological decline. Specialized proresolving lipid mediators (SPMs) are endogenous autacoids that actively promote resolution of inflammation. In this study, we investigated resolution of acute inflammation in aging and the roles of SPMs. Using a self-resolving peritonitis and resolution indices coupled with lipid mediator metabololipidomics, we found that aged mice had both delayed resolution and reduced SPMs. The SPM precursor docosahexaenoic acid accelerated resolution via increased SPMs and promoted human monocyte reprogramming. In aged mice, novel nanoproresolving medicines carrying aspirin-triggered resolvins D1 and D3 reduced inflammation by promoting efferocytosis. These findings provide evidence for age-dependent resolution pathways in acute inflammation and novel means to activate resolution. The Journal of Immunology , 2014, 193: 000–000. age is associated with heightened proinflammatory status with elevated levels of TNF- a , IL-1 b , and IL-6, which contribute to the age-related decline of physiological functions (8). There-fore, we hypothesized that endogenous resolution programs and specifically proresolving lipid mediators may be dysregulated during aging. To address this, in the present study we used a systems approach with LM metabololipidomics to investigate whether age impacts resolution of acute inflammation. Our findings demonstrated in aged mice that exudate SPMs are reduced, inflammation is heightened, and resolution is delayed. This resolution delay was rescued with SPMs (i.e., RvD3), SPM precursors, and nano-proresolving medicine (NPRM) carrying aspirin-triggered (AT) RvD1 and AT-RvD3 (Resolvin-NPRM).

[1]  T. Harrer,et al.  Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines , 2014, Nature Medicine.

[2]  Ruth R. Montgomery,et al.  Age-dependent dysregulation of innate immunity , 2013, Nature Reviews Immunology.

[3]  D. Gilroy,et al.  Pathways mediating resolution of inflammation: when enough is too much , 2013, The Journal of pathology.

[4]  C. Serhan,et al.  Resolution phase lipid mediators of inflammation: agonists of resolution. , 2013, Current opinion in pharmacology.

[5]  J. Haeggström,et al.  The novel 13S,14S ‐epoxy‐maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  S. Gordon,et al.  Tissue macrophage heterogeneity: issues and prospects , 2013, Seminars in Immunopathology.

[7]  D. Cai,et al.  Hypothalamic Programming of Systemic Aging Involving IKKβ/NF-κB and GnRH , 2013, Nature.

[8]  W. Zhou,et al.  Resolvin D1, an Endogenous Lipid Mediator for Inactivation of Inflammation‐Related Signaling Pathways in Microglial Cells, Prevents Lipopolysaccharide‐Induced Inflammatory Responses , 2013, CNS neuroscience & therapeutics.

[9]  Y. Kawaoka,et al.  The Lipid Mediator Protectin D1 Inhibits Influenza Virus Replication and Improves Severe Influenza , 2013, Cell.

[10]  P. Calder.  Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? , 2013, British journal of clinical pharmacology.

[11]  Ira Tabas,et al.  Anti-Inflammatory Therapy in Chronic Disease: Challenges and Opportunities , 2013, Science.

[12]  Elisabeth Wong,et al.  Microfluidic chambers for monitoring leukocyte trafficking and humanized nano-proresolving medicines interactions , 2012, Proceedings of the National Academy of Sciences.

[13]  S. Dakin,et al.  Inflamm-Aging and Arachadonic Acid Metabolite Differences with Stage of Tendon Disease , 2012, PloS one.

[14]  M. Giera,et al.  Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. , 2012, Biochimica et biophysica acta.

[15]  C. Serhan,et al.  Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. , 2012, Blood.

[16]  Trevor A. Mori,et al.  Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. , 2012, Clinical chemistry.

[17]  Charles N. Serhan,et al.  Infection Regulates Pro-Resolving Mediators that Lower Antibiotic Requirements , 2012, Nature.

[18]  Alberto Mantovani,et al.  Macrophage plasticity and polarization: in vivo veritas. , 2012, The Journal of clinical investigation.

[19]  Ruth C Lovering,et al.  Transcriptomic analyses of murine resolution-phase macrophages. , 2011, Blood.

[20]  V. Arroyo,et al.  Resolvin D1 and Its Precursor Docosahexaenoic Acid Promote Resolution of Adipose Tissue Inflammation by Eliciting Macrophage Polarization toward an M2-Like Phenotype , 2011, The Journal of Immunology.

[21]  E. Motta,et al.  The precursor of resolvin D series and aspirin‐triggered resolvin D1 display anti‐hyperalgesic properties in adjuvant‐induced arthritis in rats , 2011, British journal of pharmacology.

[22]  Yunan Tang,et al.  Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese‐diabetic mice , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  K. Swedberg.  n-3 Fatty acids in cardiovascular disease. , 2011, The New England journal of medicine.

[24]  M. Perretti,et al.  Cutting Edge: Humanized Nano-Proresolving Medicines Mimic Inflammation-Resolution and Enhance Wound Healing , 2011, The Journal of Immunology.

[25]  C. Serhan,et al.  Saturated‐efferocytosis generates pro‐resolving CD11blow macrophages: Modulation by resolvins and glucocorticoids , 2011, European journal of immunology.

[26]  M. Perretti,et al.  Fundamentals of Inflammation: Models of Acute Inflammation – Air-Pouch, Peritonitis, and Ischemia-Reperfusion , 2010 .

[27]  M. Pomponi,et al.  Alzheimer's Disease: Fatty Acids We Eat may be Linked to a Specific Protection via Low-dose Aspirin. , 2010, Aging and disease.

[28]  Charles N. Serhan,et al.  Resolvin E1 and protectin D1 activate inflammation-resolution programmes , 2007, Nature.

[29]  C. Serhan,et al.  Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression , 2006, Nature Immunology.

[30]  G. Davı̀,et al.  Aging is characterized by a profound reduction in anti-inflammatory lipoxin A4 levels , 2005, Experimental Gerontology.

[31]  Shubhada Sankararaman,et al.  Cells, tissues and disease: Principles of general pathology , 1997 .

[32]  C. Serhan,et al.  Resolvins , 2002, The Journal of experimental medicine.

[33]  J. Morrow,et al.  Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. , 1994, The Journal of biological chemistry.

[34]  P. Poubelle,et al.  Intraperitoneal injection of zymosan in mice induces pain, inflammation and the synthesis of peptidoleukotrienes and prostaglandin E2. , 1985, Prostaglandins.