Malaria Pigment Hemozoin Impairs GM-CSF Receptor Expression and Function by 4-Hydroxynonenal.

Evelin Schwarzer,Giorgia Mandili,Valentina Barrera,Elena Valente,Daniela Ulliers,Oleksii Skorokhod,Federica Costanza

doi:10.3390/antiox10081259

Abstract

Malarial pigment hemozoin (HZ) generates the lipoperoxidation product 4-hydroxynonenal (4-HNE), which is known to cause dysregulation of the immune response in malaria. The inhibition of granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent differentiation of dendritic cells (DC) by HZ and 4-HNE was previously described in vitro, and the GM-CSF receptor (GM-CSF R) was hypothesised to be a primary target of 4-HNE in monocytes. In this study, we show the functional impact of HZ on GM-CSF R in monocytes and monocyte-derived DC by (i) impairing GM-CSF binding by 50 ± 9% and 65 ± 14%, respectively (n = 3 for both cell types); (ii) decreasing the expression of GM-CSF R functional subunit (CD116) on monocyte’s surface by 36 ± 11% (n = 6) and in cell lysate by 58 ± 16% (n = 3); and (iii) binding of 4-HNE to distinct amino acid residues on CD116. The data suggest that defective DC differentiation in malaria is caused by GM-CSF R dysregulation and GM-CSF R modification by lipoperoxidation product 4-HNE via direct interaction with its CD116 subunit.

Highlights

Malaria is still the most important life-threatening parasitic disease according to the World Health Organisation report, with an estimated 229 million cases and 409,000 deaths occurring in 2019
The observed modifications of granulocyte macrophage colony-stimulating factor (GM-CSF) R may contribute to gain insight into the inadequate immune response described in malaria
Described phagocytosis of HZ, neutral latex beads, and red blood cell (RBC) by monocytes was confirmed by microscopic examination and biochemical luminescence analysis

Summary

Introduction

Malaria is still the most important life-threatening parasitic disease according to the World Health Organisation report, with an estimated 229 million cases and 409,000 deaths occurring in 2019. Human monocytes are strongly activated by their first HZ contact, avidly phagocytose HZ [13,14], and produce pro-inflammatory cytokines and ROS. This initial hyperactive state of the monocytic cells is transient and replaced after few hours by the permanent inhibition of various important immune cell functions, such as motility [15], respiratory (oxidative) burst, further phagocytosis cycles [16], antigen presentation, and the ability to differentiate to macrophages or dendritic cells (DC) [14,17,18,19,20] caused by the persistence of HZ in lysosomes.

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Conclusion