Background The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated. Methods We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line. Results The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling. Conclusion Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria.
References
[1]
Balachandar S, Katyal A (2010) Peroxisome proliferator activating receptor (PPAR) in cerebral malaria (CM): a novel target for an additional therapy. Eur J Clin Microbiol Infect Dis.
[2]
Taoufiq Z, Gay F, Balvanyos J, Ciceron L, Tefit M, et al. (2008) Rho kinase inhibition in severe malaria: thwarting parasite-induced collateral damage to endothelia. J Infect Dis 197: 1062–1073.
[3]
Armah HB, Wilson NO, Sarfo BY, Powell MD, Bond VC, et al. (2007) Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children. Malar J 6: 147.
[4]
Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, et al. (2007) Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13: 703–710.
[5]
Pamplona A, Hanscheid T, Epiphanio S, Mota MM, Vigario AM (2009) Cerebral malaria and the hemolysis/methemoglobin/heme hypothesis: shedding new light on an old disease. Int J Biochem Cell Biol 41: 711–716.
[6]
Epiphanio S, Campos MG, Pamplona A, Carapau D, Pena AC, et al. (2010) VEGF promotes malaria-associated acute lung injury in mice. PLoS Pathog 6: e1000916.
[7]
Hunt NH, Stocker R (2007) Heme moves to center stage in cerebral malaria. Nat Med 13: 667–669.
[8]
Datta D, Banerjee P, Gasser M, Waaga-Gasser AM, Pal S (2010) CXCR3-B can mediate growth-inhibitory signals in human renal cancer cells by downregulating the expression of heme oxygenase-1. J Biol Chem.
[9]
Geuken E, Buis CI, Visser DS, Blokzijl H, Moshage H, et al. (2005) Expression of heme oxygenase-1 in human livers before transplantation correlates with graft injury and function after transplantation. Am J Transplant 5: 1875–1885.
[10]
Bussolati B, Mason JC (2006) Dual role of VEGF-induced heme-oxygenase-1 in angiogenesis. Antioxid Redox Signal 8: 1153–1163.
[11]
Pae HO, Oh GS, Choi BM, Kim YM, Chung HT (2005) A molecular cascade showing nitric oxide-heme oxygenase-1-vascular endothelial growth factor-interleukin-8 sequence in human endothelial cells. Endocrinology 146: 2229–2238.
[12]
Datta D, Dormond O, Basu A, Briscoe DM, Pal S (2007) Heme oxygenase-1 modulates the expression of the anti-angiogenic chemokine CXCL-10 in renal tubular epithelial cells. Am J Physiol Renal Physiol 293: F1222–1230.
[13]
Hanum PS, Hayano M, Kojima S (2003) Cytokine and chemokine responses in a cerebral malaria-susceptible or -resistant strain of mice to Plasmodium berghei ANKA infection: early chemokine expression in the brain. Int Immunol 15: 633–640.
[14]
Colvin RA, Campanella GS, Sun J, Luster AD (2004) Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function. J Biol Chem 279: 30219–30227.
[15]
Loetscher M, Loetscher P, Brass N, Meese E, Moser B (1998) Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization. Eur J Immunol 28: 3696–3705.
[16]
Chen L, Sendo F (2001) Cytokine and chemokine mRNA expression in neutrophils from CBA/NSlc mice infected with Plasmodium berghei ANKA that induces experimental cerebral malaria. Parasitol Int 50: 139–143.
[17]
Jain V, Armah HB, Tongren JE, Ned RM, Wilson NO, et al. (2008) Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar J 7: 83.
[18]
Wilson NO, Huang MB, Anderson W, Bond V, Powell M, et al. (2008) Soluble factors from Plasmodium falciparum-infected erythrocytes induce apoptosis in human brain vascular endothelial and neuroglia cells. Mol Biochem Parasitol 162: 172–176.
[19]
Campanella GS, Tager AM, El Khoury JK, Thomas SY, Abrazinski TA, et al. (2008) Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria. Proc Natl Acad Sci U S A 105: 4814–4819.
[20]
Van den Steen PE, Deroost K, Van Aelst I, Geurts N, Martens E, et al. (2008) CXCR3 determines strain susceptibility to murine cerebral malaria by mediating T lymphocyte migration toward IFN-gamma-induced chemokines. Eur J Immunol 38: 1082–1095.
[21]
Miu J, Mitchell AJ, Muller M, Carter SL, Manders PM, et al. (2008) Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency. J Immunol 180: 1217–1230.
[22]
Nie CQ, Bernard NJ, Norman MU, Amante FH, Lundie RJ, et al. (2009) IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection. PLoS Pathog 5: e1000369.
[23]
Hansen DS, Bernard NJ, Nie CQ, Schofield L (2007) NK cells stimulate recruitment of CXCR3+ T cells to the brain during Plasmodium berghei-mediated cerebral malaria. J Immunol 178: 5779–5788.
[24]
Hansen DS, Siomos MA, Buckingham L, Scalzo AA, Schofield L (2003) Regulation of murine cerebral malaria pathogenesis by CD1d-restricted NKT cells and the natural killer complex. Immunity 18: 391–402.
[25]
Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, et al. (2001) CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med 193: 471–481.
[26]
Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, et al. (2003) IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4: 551–556.
[27]
Williams L, Bradley L, Smith A, Foxwell B (2004) Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol 172: 567–576.
[28]
Murray PJ (2006) Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol 6: 379–386.
[29]
Yoshimura A (2009) Regulation of cytokine signaling by the SOCS and Spred family proteins. Keio J Med 58: 73–83.
[30]
Labbe K, Miu J, Yeretssian G, Serghides L, Tam M, et al. (2010) Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling. J Immunol 185: 5495–5502.
[31]
Tripathi AK, Sha W, Shulaev V, Stins MF, Sullivan DJ Jr (2009) Plasmodium falciparum-infected erythrocytes induce NF-kappaB regulated inflammatory pathways in human cerebral endothelium. Blood 114: 4243–4252.
[32]
Gillrie MR, Krishnegowda G, Lee K, Buret AG, Robbins SM, et al. (2007) Src-family kinase dependent disruption of endothelial barrier function by Plasmodium falciparum merozoite proteins. Blood 110: 3426–3435.
[33]
Yipp BG, Robbins SM, Resek ME, Baruch DI, Looareesuwan S, et al. (2003) Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow. Blood 101: 2850–2857.
[34]
Zhang Z, Fuller GM (1997) The competitive binding of STAT3 and NF-kappaB on an overlapping DNA binding site. Biochem Biophys Res Commun 237: 90–94.
[35]
White NJ, Turner GD, Medana IM, Dondorp AM, Day NP (2010) The murine cerebral malaria phenomenon. Trends Parasitol 26: 11–15.
[36]
Baptista FG, Pamplona A, Pena AC, Mota MM, Pied S, et al. (2010) Accumulation of Plasmodium berghei-infected red blood cells in the brain is crucial for the development of cerebral malaria in mice. Infect Immun 78: 4033–4039.
[37]
Shi X, Qin L, Liu G, Zhao S, Peng N, et al. (2008) Dynamic balance of pSTAT1 and pSTAT3 in C57BL/6 mice infected with lethal or nonlethal Plasmodium yoelii. Cell Mol Immunol 5: 341–348.
[38]
Zhu J, Wu X, Goel S, Gowda NM, Kumar S, et al. (2009) MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-induced production of tumor necrosis factor-{alpha} and interleukin-12 in macrophages. J Biol Chem 284: 15750–15761.
[39]
Mohan A, Sharma SK, Bollineni S (2008) Acute lung injury and acute respiratory distress syndrome in malaria. J Vector Borne Dis 45: 179–193.
[40]
Ehrich JH, Eke FU (2007) Malaria-induced renal damage: facts and myths. Pediatr Nephrol 22: 626–637.
[41]
Nguansangiam S, Day NP, Hien TT, Mai NT, Chaisri U, et al. (2007) A quantitative ultrastructural study of renal pathology in fatal Plasmodium falciparum malaria. Trop Med Int Health 12: 1037–1050.
[42]
Belcher JD, Mahaseth H, Welch TE, Otterbein LE, Hebbel RP, et al. (2006) Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. J Clin Invest 116: 808–816.
[43]
Belcher JD, Vineyard JV, Bruzzone CM, Chen C, Beckman JD, et al. (2010) Heme oxygenase-1 gene delivery by Sleeping Beauty inhibits vascular stasis in a murine model of sickle cell disease. J Mol Med 88: 665–675.
[44]
Takeda M, Kikuchi M, Ubalee R, Na-Bangchang K, Ruangweerayut R, et al. (2005) Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to cerebral malaria in Myanmar. Jpn J Infect Dis 58: 268–271.
[45]
Lin Q, Weis S, Yang G, Weng YH, Helston R, et al. (2007) Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress. J Biol Chem 282: 20621–20633.
[46]
Ryter SW, Choi AM (2009) Heme oxygenase-1/carbon monoxide: from metabolism to molecular therapy. Am J Respir Cell Mol Biol 41: 251–260.
[47]
Kim HP, Wang X, Galbiati F, Ryter SW, Choi AM (2004) Caveolae compartmentalization of heme oxygenase-1 in endothelial cells. FASEB J 18: 1080–1089.
[48]
Fu N, Drinnenberg I, Kelso J, Wu JR, Paabo S, et al. (2007) Comparison of protein and mRNA expression evolution in humans and chimpanzees. PLoS One 2: e216.
[49]
Delahaye NF, Coltel N, Puthier D, Barbier M, Benech P, et al. (2007) Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice. BMC Genomics 8: 452.
[50]
Delahaye NF, Coltel N, Puthier D, Flori L, Houlgatte R, et al. (2006) Gene-expression profiling discriminates between cerebral malaria (CM)-susceptible mice and CM-resistant mice. J Infect Dis 193: 312–321.
[51]
Lamikanra AA, Brown D, Potocnik A, Casals-Pascual C, Langhorne J, et al. (2007) Malarial anemia: of mice and men. Blood 110: 18–28.
[52]
Asami M, Owhashi M, Abe T, Nawa Y (1992) A comparative study of the kinetic changes of hemopoietic stem cells in mice infected with lethal and non-lethal malaria. Int J Parasitol 22: 43–47.
[53]
Maggio-Price L, Brookoff D, Weiss L (1985) Changes in hematopoietic stem cells in bone marrow of mice with Plasmodium berghei malaria. Blood 66: 1080–1085.
[54]
Belnoue E, Potter SM, Rosa DS, Mauduit M, Gruner AC, et al. (2008) Control of pathogenic CD8+ T cell migration to the brain by IFN-gamma during experimental cerebral malaria. Parasite Immunol 30: 544–553.
[55]
Ke B, Shen XD, Gao F, Ji H, Qiao B, et al. (2010) Adoptive transfer of ex vivo HO-1 modified bone marrow-derived macrophages prevents liver ischemia and reperfusion injury. Mol Ther 18: 1019–1025.
[56]
Tsuchihashi S, Zhai Y, Bo Q, Busuttil RW, Kupiec-Weglinski JW (2007) Heme oxygenase-1 mediated cytoprotection against liver ischemia and reperfusion injury: inhibition of type-1 interferon signaling. Transplantation 83: 1628–1634.
[57]
Tsuchihashi S, Zhai Y, Fondevila C, Busuttil RW, Kupiec-Weglinski JW (2005) HO-1 upregulation suppresses type 1 IFN pathway in hepatic ischemia/reperfusion injury. Transplant Proc 37: 1677–1678.
[58]
Kotsch K, Martins PN, Klemz R, Janssen U, Gerstmayer B, et al. (2007) Heme oxygenase-1 ameliorates ischemia/reperfusion injury by targeting dendritic cell maturation and migration. Antioxid Redox Signal 9: 2049–2063.
[59]
El Kasmi KC, Holst J, Coffre M, Mielke L, de Pauw A, et al. (2006) General nature of the STAT3-activated anti-inflammatory response. J Immunol 177: 7880–7888.
[60]
Yu H, Jove R (2004) The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 4: 97–105.
[61]
Milner DA Jr (2010) Rethinking cerebral malaria pathology. Curr Opin Infect Dis 23: 456–463.
[62]
Sarfo BY, Wilson NO, Bond VC, Stiles JK (2011) Plasmodium berghei ANKA infection increases Foxp3, IL-10 and IL-2 in CXCL-10 deficient C57BL/6 mice. Malar J 10: 69.
