Language
English
Publication Date
7-14-2025
Journal
Immunohorizons
DOI
10.1093/immhor/vlaf028
PMID
40694828
PMCID
PMC12282984
PubMedCentral® Posted Date
7-22-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Immune dysfunction and late mortality from multiorgan failure are hallmarks of severe sepsis. Arginine, a semi-essential amino acid important for protein synthesis, immune response, and circulatory regulation, is deficient in sepsis. However, arginine supplementation in sepsis remains controversial due to the potential to upregulate inducible nitric oxide synthase (iNOS)-mediated excessive nitric oxide (NO) generation in macrophages, leading to vasodilation and hemodynamic catastrophe. Citrulline supplementation has been considered an alternative to replenishing arginine via de novo synthesis, orchestrated by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). However, the functional relevance of the ASS1-ASL pathway in macrophages after endotoxin stimulation is unclear but it is crucial to consider amino acid restoration as a tool for treating sepsis. We demonstrate that lipopolysaccharide (LPS)-mediated iNOS, ASS1, and ASL protein expression and nitric oxide generation were dependent on exogenous arginine in RAW 264.7 macrophages. Exogenous citrulline was not sufficient to restore nitric oxide generation in arginine-free conditions. Despite the induction of iNOS and ASS1 mRNA in arginine-free conditions, exogenous arginine was necessary and citrulline was not sufficient to overcome eIF2-α (elongation initiation factor 2-α)-mediated translational repression of iNOS and ASS1 protein expression. Moreover, exogenous arginine, but not citrulline, selectively modified the inflammatory cytokine and chemokine expression profile of the LPS-activated RAW 264.7 and bone marrow-derived macrophages. Our study highlights the complex, differential regulation of proinflammatory cytokine expression, and NO generation by exogenous arginine in macrophages.
Keywords
Animals, Mice, Nitric Oxide Synthase Type II, Arginine, Macrophages, Argininosuccinate Synthase, Lipopolysaccharides, Cytokines, Nitric Oxide, RAW 264.7 Cells, Citrulline, Argininosuccinate Lyase, Mice, Inbred C57BL, cell activation, cytokines, endotoxin shock, monocytes/macrophages, nitric oxide
Published Open-Access
yes
Recommended Citation
Stayer, Kelsey; Pathan, Saliha; Biswas, Aalekhya; et al., "Exogenous Arginine Differentially Regulates Inflammatory Cytokine and Inducible Nitric Oxide Synthase Expression in Macrophages" (2025). Faculty and Staff Publications. 4950.
https://digitalcommons.library.tmc.edu/baylor_docs/4950
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons