AUTHOR=Álvarez Enrique , Toledano Víctor , Morilla Fernando , Hernández-Jiménez Enrique , Cubillos-Zapata Carolina , Varela-Serrano Aníbal , Casas-Martín José , Avendaño-Ortiz José , Aguirre Luis A. , Arnalich Francisco , Maroun-Eid Charbel , Martín-Quirós Alejandro , Quintana Díaz Manuel , López-Collazo Eduardo TITLE=A System Dynamics Model to Predict the Human Monocyte Response to Endotoxins JOURNAL=Frontiers in Immunology VOLUME=8 YEAR=2017 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00915 DOI=10.3389/fimmu.2017.00915 ISSN=1664-3224 ABSTRACT=

System dynamics is a powerful tool that allows modeling of complex and highly networked systems such as those found in the human immune system. We have developed a model that reproduces how the exposure of human monocytes to lipopolysaccharides (LPSs) induces an inflammatory state characterized by high production of tumor necrosis factor alpha (TNFα), which is rapidly modulated to enter into a tolerant state, known as endotoxin tolerance (ET). The model contains two subsystems with a total of six states, seven flows, two auxiliary variables, and 14 parameters that interact through six differential and nine algebraic equations. The parameters were estimated and optimized to obtain a model that fits the experimental data obtained from human monocytes treated with various LPS doses. In contrast to publications on other animal models, stimulation of human monocytes with super-low-dose LPSs did not alter the response to a second LPSs challenge, neither inducing ET, nor enhancing the inflammatory response. Moreover, the model confirms the low production of TNFα and increased levels of C–C motif ligand 2 when monocytes exhibit a tolerant state similar to that of patients with sepsis. At present, the model can help us better understand the ET response and might offer new insights on sepsis diagnostics and prognosis by examining the monocyte response to endotoxins in patients with sepsis.