Cross-talk between CD38 and TTP Is Essential for Resolution of Inflammation during Microbial Sepsis

Cell Rep. 2020 Jan 28;30(4):1063-1076.e5. doi: 10.1016/j.celrep.2019.12.090.

Abstract

The resolution phase of acute inflammation is essential for tissue homeostasis, yet the underlying mechanisms remain unclear. We demonstrate that resolution of inflammation involves interactions between CD38 and tristetraprolin (TTP). During the onset of acute inflammation, CD38 levels are increased, leading to the production of Ca2+-signaling messengers, nicotinic acid adenine dinucleotide phosphate (NAADP), ADP ribose (ADPR), and cyclic ADPR (cADPR) from NAD(P)+. To initiate the onset of resolution, TTP expression is increased by the second messengers, NAADP and cADPR, which downregulate CD38 expression. The activation of TTP by Sirt1-dependent deacetylation, in response to increased NAD+ levels, suppresses the acute inflammatory response and decreases Rheb expression, inhibits mTORC1, and induces autophagolysosomes for bacterial clearance. TTP may represent a mechanistic target of anti-inflammatory agents, such as carbon monoxide. TTP mediates crosstalk between acute inflammation and autophagic clearance of bacteria from damaged tissue in the resolution of inflammation during sepsis.

Keywords: CD38; Rheb; Sirt1; acute inflammation; autophagolysosome; resolution of inflammation; sepsis; tristetraprolin.

MeSH terms

  • ADP-ribosyl Cyclase 1 / genetics
  • ADP-ribosyl Cyclase 1 / immunology*
  • ADP-ribosyl Cyclase 1 / metabolism
  • Adenosine Diphosphate Ribose / metabolism
  • Animals
  • Autophagosomes / drug effects
  • Autophagosomes / immunology
  • Autophagosomes / metabolism
  • Autophagosomes / microbiology
  • Calcium / metabolism
  • Carbon Monoxide / metabolism
  • Carbon Monoxide / pharmacology
  • Cell Line
  • Disease Models, Animal
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NAD / metabolism
  • NADP / metabolism
  • RNA, Small Interfering
  • Ras Homolog Enriched in Brain Protein / metabolism
  • Sepsis / enzymology
  • Sepsis / immunology
  • Sepsis / metabolism*
  • Sirtuin 1 / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Tristetraprolin / genetics
  • Tristetraprolin / metabolism*

Substances

  • Lipopolysaccharides
  • Membrane Glycoproteins
  • RNA, Small Interfering
  • Ras Homolog Enriched in Brain Protein
  • Tristetraprolin
  • NAD
  • Adenosine Diphosphate Ribose
  • NADP
  • Carbon Monoxide
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Cd38 protein, mouse
  • ADP-ribosyl Cyclase 1
  • Sirtuin 1
  • Calcium