Involvement of Nod2 in the innate immune response elicited by malarial pigment hemozoin

Abstract

In malaria, the evidence concerning the nucleotide-binding, oligomerization domain (NOD) 2 (NOD2) receptor is fragmented and the stimuli that might activate NOD2 are not well characterized. We investigated the role of NOD2 in vitro in the response of macrophages to Plasmodium falciparum products. Immortalized or primary bone marrow derived macrophages from wild type C57Bl/6 mice, or knockout mice for NOD2 or its adaptor proteins, were either primed with interferon gamma or left untreated, and stimulated with parasite products. Both lysates of infected erythrocytes or hemozoin induced higher levels of nitric oxide in primed than in unprimed wild type macrophages. When stimulated with hemozoin, primed macrophages knockout for NOD2, or for its adaptor proteins, produced significantly lower nitric oxide levels compared to wild type cells. Differently from hemozoin, the use of β-hematin (synthetic hemozoin) as stimulus showed that NOD2 is dispensable. Furthermore, the production of inflammatory cytokines by wild type cells treated with hemozoin was not dependent on NOD2. These data indicate that parasite components present in the hemozoin, differently from β-hematin, induce the production of nitric oxide through the activation of NOD2, whereas the production of inflammatory cytokines, like TNF-α or MIP-2 (CXCL2), seems to be NOD2 independent.

NOD1 and NOD2: Beyond Peptidoglycan Sensing

“…In a model of malaria utilizing Plasmodium berghei , mice deficient for NOD1 and NOD2 exhibited decreased inflammatory cytokine responses, but no difference in control of the parasite or development of lethal disease [63]. Work in a cellular model suggests that an unidentified ligand from P. falciparum -infected erythrocytes, that co-purifies with the parasite product hemozoin, stimulates NOD2 in a RIP2/CARD9-dependent manner to drive nitric oxide production by macrophages, however the identity of the stimulatory ligand and its mechanism of NOD2 activation remains to be determined [64]. In the case of infection with Trypanosoma cruzi , mice deficient for NOD1, but not for NOD2, succumbed more rapidly to parasite infection and failed to control parasite replication in the spleen and heart [65].…”

Nucleotide-binding oligomerization domain-containing protein 2 prompts potent inflammatory stimuli during Neospora caninum infection

“…While Nod1 is ubiquitously expressed, Nod2 is expressed in hematopoietic cells, and both cooperate to signal via the adaptor molecule Receptor-Interacting Protein 2 (Rip2), a serine-threonine kinase required for activation of NF-κB and mitogen-activated protein kinase (MAPK) cascades that culminate with the upregulation of proinflammatory genes 18 19 20 . Nod2 is involved in the recognition of active moieties of bacterial cell wall peptidoglycan, muramyl dipeptide (MDP), and previous studies state that this receptor may be crucial to host defense against infections by parasites and viruses 19 21 22 23 24 . Also, it has been proposed that Nod2 is necessary for generating protective Th1 immunity against T. gondii, a protozoan parasite closely related with N. caninum 22 .…”

Heme-mediated apoptosis and fusion damage in BeWo trophoblast cells

“…Extraction of hemozoin from perfused mouse tissues was performed as described previously2063. Briefly, approximately 60 mg liver was homogenized with a solution containing 50 mM Tris/HCl pH 8.0, 5 mM CaCl 2 , 50 mM NaCl and 1% Triton X-100.…”