Download PDF
Thromb Haemost 2020; 120(04): 658-670
DOI: 10.1055/s-0040-1703007
Blood Cells, Inflammation and Infection
Georg Thieme Verlag KG Stuttgart · New York

Thrombin Promotes Macrophage Polarization into M1-Like Phenotype to Induce Inflammatory Responses

Mercedes López-Zambrano   *
1   Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela
2   Department of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany
,
Julián Rodriguez-Montesinos   *
2   Department of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany
,
Gustavo E. Crespo-Avilan
2   Department of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany
3   Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore
,
Mónica Muñoz-Vega
4   Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Unidad de Investigación de Enfermedades Metabólicas, Mexico City, Mexico
,
Klaus T. Preissner
2   Department of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany
5   Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russian Federation
› Author Affiliations
Further Information

Publication History

01 August 2019

24 January 2020

Publication Date:
04 March 2020 (online)

Also available at
   Buy Article Permissions and Reprints
Zoom Image

Abstract

Despite strong evidence supporting the cellular interplay between haemostasis and innate immunity, humoral connections between blood coagulation and the behavior of inflammatory macrophages are not well understood. In this study, we investigated changes in gene expression of selected cytokines and chemokines and their secretion profiles following thrombin stimulation of murine macrophages. Thrombin promoted differentiation of macrophages into an M1-like phenotype that was associated with the expression of classical pro-inflammatory markers. The cellular actions of thrombin on macrophages were mediated in part by protease-activated receptor-1 (PAR-1) and were dependent on phosphoinositide 3-kinase/AKT and nuclear factor-κB. Moreover, heat-denatured thrombin stimulated the secretion of some pro-inflammatory mediators to the same magnitude indicating that different receptors transmit cellular signals of enzymatically active thrombin and nonactive thrombin, the latter remaining so far undefined. Finally, pretreatment of macrophages with thrombin resulted in tolerance against secondary stimulation by lipopolysaccharide with regard to expression of tumor necrosis factor-α. These results provide new insights into the molecular link between the key enzyme of haemostasis and innate immunity responses.

Keywords

thrombin receptors - tumor necrosis factor-α - protease-activated receptors - cytokine profile - innate immunity

Authors' Contributions

M.L.Z. and K.T.P. conceived the overall research design of the present study and wrote the manuscript. M.L.Z. and J.R.M. performed the major experiments as well as the statistical analyses. G.E.C.A. and M.M.V. performed some experiments. All authors approved the submitted version of the manuscript.


* Joint first authors.


Supplementary Material