Circulating BPIFB4 Levels Associate With and Influence the Abundance of Reparative Monocytes and Macrophages in Long Living Individuals

Front Immunol. 2020 May 29;11:1034. doi: 10.3389/fimmu.2020.01034. eCollection 2020.

Abstract

Long-Living Individuals (LLIs) delay aging and are less prone to chronic inflammatory reactions. Whether a distinct monocytes and macrophages repertoire is involved in such a characteristic remains unknown. Previous studies from our group have shown high levels of the host defense BPI Fold Containing Family B Member 4 (BPIFB4) protein in the peripheral blood of LLIs. Moreover, a polymorphic variant of the BPIFB4 gene associated with exceptional longevity (LAV-BPIFB4) confers protection from cardiovascular diseases underpinned by low-grade chronic inflammation, such as atherosclerosis. We hypothesize that BPIFB4 may influence monocytes pool and macrophages skewing, shifting the balance toward an anti-inflammatory phenotype. We profiled circulating monocytes in 52 LLIs (median-age 97) and 52 healthy volunteers (median-age 55) using flow cytometry. If the frequency of total monocyte did not change, the intermediate CD14++CD16+ monocytes counts were lower in LLIs compared to control adults. Conversely, non-classical CD14+CD16++ monocyte counts, which are M2 macrophage precursors with an immunomodulatory function, were found significantly associated with the LLIs' state. In a differentiation assay, supplementation of the LLIs' plasma enhanced the capacity of monocytes, either from LLIs or controls, to acquire a paracrine M2 phenotype. A neutralizing antibody against the phosphorylation site (ser 75) of BPIFB4 blunted the M2 skewing effect of the LLIs' plasma. These data indicate that LLIs carry a peculiar anti-inflammatory myeloid profile, which is associated with and possibly sustained by high circulating levels of BPIFB4. Supplementation of recombinant BPIFB4 may represent a novel means to attenuate inflammation-related conditions typical of unhealthy aging.

Keywords: FACS; M2 macrophages; immunity; longevity; patrolling-monocytes; plasma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged, 80 and over
  • Antibodies, Neutralizing / metabolism
  • Atherosclerosis / genetics*
  • Biomarkers / blood*
  • Cell Differentiation
  • Cells, Cultured
  • Female
  • Humans
  • Immunophenotyping
  • Intercellular Signaling Peptides and Proteins / blood*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / immunology
  • Lipopolysaccharide Receptors / metabolism
  • Longevity / physiology*
  • Macrophages / immunology*
  • Male
  • Middle Aged
  • Monocytes / immunology*
  • Polymorphism, Genetic
  • Th2 Cells / immunology

Substances

  • Antibodies, Neutralizing
  • BPIFB4 protein, human
  • Biomarkers
  • Intercellular Signaling Peptides and Proteins
  • Lipopolysaccharide Receptors