Hemozoin‐induced activation of human monocytes toward M2‐like phenotype is partially reversed by antimalarial drugs—chloroquine and artemisinin

Abstract

Plasmodium falciparum malaria is the most severe form of malaria with several complications. The malaria pigment-hemozoin (Hz) is associated with severe anemia, cytokine dysfunction, and immunosuppression, thus making it an interesting target for developing new strategies for antimalarial therapy. Monocytes (MO) in circulation actively ingest Hz released by Plasmodium parasites and secrete pro- and anti-inflammatory cytokines. M1 and M2 types represent the two major forms of MO/macrophages (MQ) with distinct phenotypes and opposing functions. Imbalance in the polarization of these types is reported in many infectious diseases. Though the association of Hz with immunosuppression is well documented, its role in activation of MO in context of M1/M2 phenotypes remains to be addressed. We report here that natural Hz drives human MO toward M2-like phenotype as evidenced by the expression of M2 signature markers. Hz-fed MO showed elevated transcript and secreted level of IL-10, CCL17, CCL1, expression of mannose-binding lectin receptor (CD206), and arginase activity. Hz attenuated HLA-DR expression, nitric oxide, and reactive oxygen species production, which are the features of M1 phenotype. Our data also implicate the involvement of p38 MAPK, PI3K/AKT, and NF-κB signaling pathways in skewing of Hz-fed MO toward M2-like type and suppression of mitogen-stimulated lymphocyte proliferation. Importantly, antimalarial drugs-chloroquine and artemisinin-partially reversed activation of Hz-induced MO toward M2-like phenotype. Considering the limitations in the current therapeutic options for malaria, we propose that these drugs may be re-examined for their potential as immunomodulators and candidates for adjunctive treatment in malaria.

The immunomodulatory potential of the arylmethylaminosteroid sc1o

“…These data indicate that sc1o probably alters the energy metabolism of MdMs, leading to the promotion of an M1-phenotype in M1 and M2 MdMs. In malaria infections, an imbalance between the M1 and M2 phenotype in monocytes in favour of the M2 phenotype is observed [7]. The strengthening of the M2 phenotype is probably due to haemozoin, a malaria pigment that is involved in the breakdown of human haemoglobin by the parasites and that is linked to numerous immunological effects [8].…”

“…The strengthening of the M2 phenotype is probably due to haemozoin, a malaria pigment that is involved in the breakdown of human haemoglobin by the parasites and that is linked to numerous immunological effects [ 8 ]. The administration of haemozoin increased the expression of the resolution-promoting surface receptor CD206 as well as the secretion of the cyto- and chemokines IL-10, CCL17, and CCL1 in human monocytes [ 7 ]. Furthermore, the M1 phenotype is suppressed due to less NO and ROS formation.…”

“…Reports relating to artemisinin-resistant parasites stress the urgent need for new therapeutic approaches [5,6]. Besides resistance mechanisms against the drugs, Plasmodium further accentuates the challenge as it reduces the defensive pro-inflammatory conditions of the host by promoting the M2-phenotype of monocytes, probably through haemozoin-induced CD206 expression [7,8]. In addition to the direct impact of new drug candidates on pathogens, maintenance and promotion of immune responses are also important to overcome emerging pathogen resistance.…”

<p>Dihydroartemisinin Prevents Progression and Metastasis of Head and Neck Squamous Cell Carcinoma by Inhibiting Polarization of Macrophages in Tumor Microenvironment</p>

“…54 In a study of the parasitic disease malaria, the malarial pigment hemoglobin (Hz), a heme metabolite produced by Plasmodium, was found to induce human M0 macrophages to polarize into M2 macrophages under physiological conditions. 55 Further, the combination of chloroquine and artemisinin can inhibit M2 macrophage polarization by blocking activation of the NF-κB and PI3K/Akt pathways. These findings suggest that dihydroartemisinin as a derivative of artemisinin could inhibit M2 macrophage polarization by blocking activation of the NF-κB and PI3K/Akt pathways, which might also be happening in tumor microenvironment.…”

Circulating Monocytes, Tissue Macrophages, and Malaria

“…Hemozoin, also called malaria pigment, is the end product of erythrocyte catabolism by Plasmodium parasites. Ingestion of hemozoin by monocytes/macrophages increased the secretion of IL-10, chemokine ligand 1 (CCL1), and CCL17 and expression of the mannose binding lectin receptor (CD206) [28]. The level of IL-10 secretion was found to be positively correlated with hemozoin amount in the monocytes/macrophages [29].…”