Blood brain barrier disruption in cerebral malaria: Beyond endothelial cell activation
Fig 2
Modulators of endothelial cell cross talk with pericytes and astrocytes that may be relevant in BBB disruption during CM.
Surface adhesion molecule ICAM-1 and EPCR are known molecules facilitating binding of PfEMP-1 expressed on iRBCs. Induction of a signaling cascade triggers the transcription of TNF family members and chemokines. Binding of TNFR-2 and LT-βR activates the NF-κB pathway, inducing the CXCL10 and CCL2 recruit immune cells, such as CD8+ T cells. Barrier integrity is maintained by tight junction proteins (claudins and occludins) and adherens junction proteins (cadherins and catenins). Pericytes are recruited and maintained at the BBB by the PDGFβ-PDGFRβ signaling axis. Pericyte production of TGF-β promotes adhesion of endothelial cells to the basement membrane via induction of N-cadherin and up-regulates claudin-5 as well as down-regulates the inflammatory capacity of astrocytes. apoE is hypothesized to down-regulate pericyte-induced regulation of endothelial cell tight junctions. Astrocytes can be pro-inflammatory, secreting a variety of cytokine and chemokines that include CXCL10, CCL2, IL-6, IL-1β, IFNs, and growth factors such as VEGF. The expression of cytokine receptors such as the IL-6R/gp130 complex and IFNAR facilitate responses of astrocytes in the context of an inflammatory response. During inflammation, astrocytes form a physical barrier at the BBB via claudin 1/4 in a structure called the glial limitans perivascularis, which regulates immune cell and molecule trafficking. Astrocytes are implicated in regulating BBB integrity via Ang-I/II derived from secreted angiotensinogen. Ang-II promotes the formation and maintenance of endothelial tight junctions via binding to the AT-1 expressed on endothelial cells. SHH is also secreted from astrocytes and has been shown to up-regulate occludin and claudin-5 on BMECs by signaling through the PTCH1 receptor. BDNF and GDNF are important for growth and survival factors secreted from astrocytes, and BDNF is reported to be reduced in the peripheral blood stream of CM patients. Ang-I/II, angiopoietin-I/II; apoE, apolipoprotein E; AT-1, angiotensin II receptor type 1; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; BMEC, brain microvascular endothelial cell; CCL2, C-C Motif Chemokine Ligand 2; CD8+, cluster of differentiation 8+; CM, cerebral malaria; CXCL10, chemokines interferon-γ inducible protein 10 kDa; EPCR, endothelial protein C receptor; GDNF, glial cell line-derived neurotrophic factor; gp130, glycoprotein 130 kDa; ICAM-1, intercellular adhesion molecule 1; IFN, interferon; IFNAR, IFN-α receptor; IL, interleukin; IL-6R, interleukin-5 receptor; iRBC, infected red blood cell; LT-α, lymphotoxin-α; LT-βR, lymphotoxin-β receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PDGFβ, platelet-derived growth factor-β; PDGFRβ, platelet-derived growth factor subunit B receptor; PfEMP-1, Plasmodium falciparum erythrocyte membrane protein 1; PTCH1, Patched; SHH, Sonic hedgehog; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor; TNF-α, tumor necrosis factor-α; TNFR-2, TNF receptor 2; VE-cadherin, vascular-endothelial cadherin; VEGF, vascular endothelial cell growth factor.