Abstract
Understanding the molecular defense mechanism of macrophages and identifying their effector molecules against malarial parasites may provide important clues for the discovery of new therapies. To analyze the immunological responses of malarial parasite-induced macrophages, we used DNA microarray technology to examine the gene profile of differentiated macrophages phagocytizing Plasmodium falciparum-parasitized erythrocytes (iRBC). The transcriptional gene profile of macrophages in response to iRBCs represented 168 down-regulated genes, which were mainly involved in the cellular immune response, and 216 upregulated genes, which were involved in cellular proteolysis, growth, and adhesion. Importantly, the specific upregulation of β-defensin 130 (DEFB130) in these macrophages suggested a possible role for DEFB130 in malarial parasite elimination. Differentiated macrophages phagocytizing iRBCs exhibited an increase in intracellular DEFB130 levels and DEFB130 appeared to accumulate at the site of iRBC engulfment. Transfection of esiRNA-mediated knockdown of DEFB130 into macrophages resulted in a remarkable reduction in their antiplasmodial activity in vitro. Furthermore, DEFB130 synthetic peptide exhibited a modest toxic effect on P. falciparum in vitro and P. yoelii in vivo, unlike scrambled DEFB130 peptide, which showed no antiplasmodial activity. Together, these results suggest that DEFB130 might be one of the macrophage effector molecules for eliminating malarial parasites. Our data broaden our knowledge of the immunological response of macrophages to iRBCs and shed light on a new target for therapeutic intervention.
Highlights
Macrophages play key roles in the innate immune response against infection through their ability to rapidly recognize, phagocytize, and kill microorganisms
Differentiated macrophages were cultured with iRBCs and their phagocytic activity was determined by counting the percentage of macrophages that engulfed iRBCs or malaria pigment (Fig. 1A) at different time points of incubation
Differentiated macrophages showed very low but detectable phagocytic activity to RBCs (Fig. 1B). These results suggest that differentiated macrophages phagocytize iRBCs and may expose their effector molecules to the engulfed iRBCs in the early stage of phagocytosis
Summary
Macrophages play key roles in the innate immune response against infection through their ability to rapidly recognize, phagocytize, and kill microorganisms. The potent antimicrobial activities of AMPs and their derivatives stem from their cationic charge, hydrophobicity, and amphipathicity. These attributes allow them to attach to and insert into membrane bilayers to form pores via barrel-stave, carpet, or toroidal-pore mechanisms. We transcriptionally analyzed a gene profile of macrophages phagocytizing iRBC in an attempt to define the macrophage molecular defense mechanism against infection. This gene profile led us to identify DEFB130 as an antimicrobial host-defense peptide against malarial parasites
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