Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction

Proc Natl Acad Sci U S A. 2022 Feb 22;119(8):e2115139119. doi: 10.1073/pnas.2115139119.

Abstract

Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and the emergence of myeloid-derived suppressor cells (MDSCs) have all been associated with persistent organ dysfunction, secondary infections, and late mortality. The mechanisms involved in MDSC-mediated T cell dysfunction during sepsis share some features with those described in malignancies such as arginine deprivation. We hypothesized that increasing arginine availability would restore T cell function and decrease sepsis-induced immunosuppression. Using a mouse model of sepsis based on cecal ligation and puncture and secondary pneumonia triggered by methicillin-resistant Staphylococcus aureus inoculation, we demonstrated that citrulline administration was more efficient than arginine in increasing arginine plasma levels and restoring T cell mitochondrial function and proliferation while reducing sepsis-induced Treg and MDSC expansion. Because there is no specific therapeutic strategy to restore immune function after sepsis, we believe that our study provides evidence for developing citrulline-based clinical studies in sepsis.

Keywords: T cell; citrulline; mitochondria; sepsis.

MeSH terms

  • Animals
  • Arginine / deficiency
  • Arginine / metabolism
  • Biological Availability
  • Citrulline / metabolism
  • Citrulline / pharmacology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Immune Tolerance / immunology
  • Immunosuppression Therapy / methods
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Myeloid-Derived Suppressor Cells / immunology
  • Sepsis / drug therapy*
  • Sepsis / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Cytokines
  • Citrulline
  • Arginine