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Resolvin D1 promotes efferocytosis in aging by limiting senescent cell-induced MerTK cleavage

Nicholas Rymut1, Justin Heinz1, Sudeshna Sadhu1

  • 1The Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|January 10, 2020
PubMed

Insights

Aging impairs inflammation resolution and efferocytosis due to reduced MerTK. Resolvin D1 (RvD1) therapy and MerTK cleavage resistance restore these functions, offering potential treatments for age-related inflammatory conditions.

Area of Science:

  • Immunology
  • Aging Research
  • Molecular Biology

Background:

  • Inflammation resolution depends on specialized pro-resolving mediators (SPMs) and pro-inflammatory factors, with efferocytosis being a key process.
  • Aging is linked to impaired inflammation resolution, accumulation of senescent cells, and defective efferocytosis.
  • Understanding the mechanisms behind aging-related inflammation resolution deficits is crucial.

Purpose of the Study:

  • To investigate the mechanisms underlying impaired inflammation resolution and efferocytosis in aging.
  • To explore the role of MerTK (Mer tyrosine kinase) in aging-related inflammation and efferocytosis.
  • To evaluate the therapeutic potential of Resolvin D1 (RvD1) and MerTK modulation in aging models.

Main Methods:

  • Utilized a hind limb ischemia-reperfusion (I/R) model to induce remote lung injury in aging mice.
  • Assessed inflammation markers, SPM:LT ratio, efferocytosis, and MerTK levels in injured lungs.
  • Employed senescent cell conditioned media (CM) to study macrophage efferocytosis defects in vitro.
  • Utilized MerTK cleavage-resistant (MerTK CR) mice to investigate MerTK's role.

Main Results:

  • Aging led to heightened lung inflammation, impaired RvD1:LTB4 ratio, defective efferocytosis, and decreased MerTK levels post-I/R.
  • RvD1 treatment mitigated lung injury in aged mice, enhanced efferocytosis, and preserved MerTK levels.
  • MerTK CR mice showed reduced neutrophil infiltration and improved efferocytosis compared to aged wild-type controls.
  • Senescent cell CM impaired macrophage efferocytosis and increased MerTK cleavage, which was prevented in MerTK CR macrophages and by RvD1 stimulation.

Conclusions:

  • Aging impairs inflammation resolution and efferocytosis through mechanisms involving increased MerTK cleavage induced by senescent cells.
  • RvD1 therapy and MerTK cleavage resistance represent potential strategies to restore efferocytosis and promote inflammation resolution in aging.
  • These findings highlight a novel therapeutic target for age-related inflammatory diseases.
Keywords:
MerTKSASPefferocytosisinflammation‐resolutionresolvin

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