The Role of Nuclear Factor Kappa B (NF-κB) in the Immune Response against Parasites

Abstract

The immune system consists of various cells, organs, and processes that interact in a sophisticated manner to defend against pathogens. Upon initial exposure to an invader, nonspecific mechanisms are raised through the activation of macrophages, monocytes, basophils, mast cells, eosinophils, innate lymphoid cells, or natural killer cells. During the course of an infection, more specific responses develop (adaptive immune responses) whose hallmarks include the expansion of B and T cells that specifically recognize foreign antigens. Cell to cell communication takes place through physical interactions as well as through the release of mediators (cytokines, chemokines) that modify cell activity and control and regulate the immune response. One regulator of cell states is the transcription factor Nuclear Factor kappa B (NF-κB) which mediates responses to various stimuli and is involved in a variety of processes (cell cycle, development, apoptosis, carcinogenesis, innate and adaptive immune responses). It consists of two protein classes with NF-κB1 (p105/50) and NF-κB2 (p100/52) belonging to class I, and RelA (p65), RelB and c-Rel belonging to class II. The active transcription factor consists of a dimer, usually comprised of both class I and class II proteins conjugated to Inhibitor of κB (IκB). Through various stimuli, IκB is phosphorylated and detached, allowing dimer migration to the nucleus and binding of DNA. NF-κB is crucial in regulating the immune response and maintaining a balance between suppression, effective response, and immunopathologies. Parasites are a diverse group of organisms comprised of three major groups: protozoa, helminths, and ectoparasites. Each group induces distinct effector immune mechanisms and is susceptible to different types of immune responses (Th₁, Th₂, Th₁₇). This review describes the role of NF-κB and its activity during parasite infections and its contribution to inducing protective responses or immunopathologies.

Keywords: NF-κB; RelA; immune response; p50; p65; parasites.

Figure 1

Schematic model of NF-κB activation through canonical and non-canonical pathways. Canonical activation involves TGF-β activated kinase-1 (TAK1) which phosphorylates Inhibitory Kappa B Kinase β (IKKβ) complexed with IKKα and IKKγ (NEMO). This leads to phosphorylation of the α Inhibitor of κB (IκBα), its detachment from the p56/p50 dimer, ubiquitination, and proteasomal degradation. Released p65/p50 dimer migrates to the nucleus and binds to DNA sequences leading to transcription of appropriate genes. During the noncanonical pathway, NF-κB-inducing kinase (NIK) phosphorylates the IKKα dimer which phosphorylates p100 leading to its disruption and release of the RelB/p52 dimer. The dimer migrates to the nucleus and regulates the transcription of particular genes.

Figure 2

The impact of Plasmodium spp., Trypanosoma cruzi, Toxoplasma gondii, and Leishmania spp. on NF-κB activity and outcomes. (A) Plasmodium spp. increase NF-κB activity in specific cell populations which is associated with pathology in the brain, inducing cerebral malaria symptoms (apoptosis in brain endothelial cells and intravascular leukocytes), and may facilitate hidden parasite populations in the spleen. Plasmodium spp. also trigger an inflammatory response in monocytes, but patients with decreased NF-κB activity in PBMCs show more severe malaria symptoms. (B) Reduced NF-κB activity facilitates infection of T. cruzi. Enhanced NF-κB activity in heart tissue during T. cruzi infections leads to heart failure. (C) RelB-deprived mice do not survive T. gondii infection. T. gondii deactivate NF-κB signaling, reducing the immune response in macrophages and neutrophils. (D) Leishmania spp. reduce NF-κB activity in infected macrophages and DC, facilitating parasite survival.

Figure 3

The impact of helminths on NF-κB activity and outcomes. (A) B. malayi infection results in decreased NF-κB activity and induces M₂ and eventually M_reg macrophages, while patients with lymphatic pathology show increased angiogenesis associated with NF-κB activation. H. polygyrus induces semi-maturation of DCs and induces Th₂ and regulatory events through modulation of NF-κB activity. Products released by T. spiralis affect NF-κB activity in LPS-activated macrophages, significantly reducing proinflammatory cytokine production. (B) T. solium larval antigens activate the NF-κB pathway in monocytes inducing chemokine release. M. corti antigens inhibit LPS-induced inflammatory phenotypes in microglia cells via NF-κB modulation. (C) F. hepatica tegumental antigens temporarily prevent LPS-induced NF-κB in DC, suppressing maturation. S. mansoni induces NF-κB activation in human hepatic stellate cells which is associated with liver fibrosis; a similar situation occurs in S. Japonicum-infected mice.