PAD4 controls chemoattractant production and neutrophil trafficking in malaria

Abstract

Peptidylarginine deiminase 4 (PAD4) is a key regulator of inflammation but its function in infections remains incompletely understood. We investigate PAD4 in the context of malaria and demonstrate a role in regulation of immune cell trafficking and chemokine production. PAD4 regulates liver immunopathology by promoting neutrophil trafficking in a Plasmodium chabaudi mouse malaria model. In human macrophages, PAD4 regulates expression of CXCL chemokines in response to stimulation with TLR ligands and P. falciparum. Using patient samples, we show that CXCL1 may be a biomarker for severe malaria. PAD4 inhibition promotes disease tolerance and may represent a therapeutic avenue in malaria.

Neutrophils in malaria: The good, the bad or the ugly?

“…Also in mice with CM, an increase in the expression of TIMP‐1 was observed in the brain 63 . CXCL1 and CXCL8, two main neutrophil‐attracting chemokines, were increased in plasma of severe malaria patients 42,64 . An association between haemozoin‐containing neutrophils and monocytes and disease severity was found in several cohorts, such as Nigerian children, Malian children and Vietnamese adults 65–67 .…”

“…In addition, knockout mice which are unable to form NETs are available, such as NE/Proteinase 3 (PR3) −/− mice 41 . Peptidyl arginine deiminase 4 (PAD4) −/− mice have also been used, but their inability to form NETs has been contested 41,42 …”

“…41 Peptidyl arginine deiminase 4 (PAD4) −/− mice have also been used, but their inability to form NETs has been contested. 41,42 In the literature, contradictory results are found on the role of neutrophils in the pathogenesis of murine malaria complications. These differences can be explained by the use of different techniques to deplete neutrophils or to block neutrophil function.…”

“…63 CXCL1 and CXCL8, two main neutrophilattracting chemokines, were increased in plasma of severe malaria patients. 42,64 An association between haemozoin-containing neutrophils and monocytes and disease severity was found in several cohorts, such as Nigerian children, Malian children and Vietnamese adults. [65][66][67] In conclusion, these studies suggest an association between neutrophil activation and disease severity in malaria.…”

Investigating a causal role for neutrophil count onP. falciparumsevere malaria: a Mendelian Randomization study

“…Plasmodium resides and proliferates in red blood cells (RBCs) and pathology is triggered by cytoadherence of infected RBCs (iRBCs) to microcapillary endothelia in different organs, which can lead to vascular occlusion and endothelial permeability [3]. Inflammation plays a key role in both facilitating iRBC sequestration [4] and in tissue damage [3,5,6]. In cerebral malaria, the deadliest form of the disease, iRBCs sequester in the neurovasculature, provoking blood brain barrier permeabilization, vascular leak and brain swelling [3].…”