CD68 acts as a major gateway for malaria sporozoite liver infection

Jae, Sung Myung; Park, Kiwon; Srinivasan, Prakash; Schindler, Christian; Rooijen, Nico van; Stins, Monique F.; Jacobs-­Lorena, Marcelo

doi:10.1084/jem.20110575

Cited by 52 publications

(75 citation statements)

References 40 publications

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“…In addition, we used PMA‐activated THP‐1 macrophages as a surrogate for Kupffer cells. Human Kupffer cells are difficult to obtain, and we were unable to find enough cells to perform our studies; however, given that CD14 and CD68 are both biomarkers of human Kupffer cells and that our cells were both CD14 and CD68 positive, we used these cells instead; others have also used these cells to study Kupffer cell biology (50). Thus, it is likely that the findings from our studies are relevant and the mechanistic studies that relate palmitate to IGFBP‐3 suppression will provide potential future opportunities to translate these into novel approaches to limit systemic and hepatic inflammation in NAFLD and metabolic syndrome.…”

Section: Resultsmentioning

confidence: 99%

Suppression of IGF binding protein‐3 by palmitate promotes hepatic inflammatory responses

et al. 2016

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IGF-binding protein-3 (IGFBP-3) is a liver-derived, anti-inflammatory molecule that is decreased in obesity, a key risk factor for nonalcoholic fatty liver disease (NAFLD). It was not known whether IGFBP-3 levels were altered in NAFLD, whether such alterations could be the result of lipotoxicity, and whether altered IGFBP-3 could affect pathways that are involved in hepatic and systemic inflammation. Serum IGFBP-3 was decreased in patients with NAFLD, whereas liver and circulating IL-8 levels were increased. Palmitate inhibited IGFBP-3 secretion by THP-1 macrophages and enhanced IL-8 expression. Exposure of palmitate-treated THP-1 macrophages to IGFBP-3-deficient conditioned medium led to a 20-fold increase in palmitate-induced IL-8 expression by hepatocytes. Conversely, overexpression of IGFBP-3 suppressed JNK and NF-κB activation and blocked palmitate-induced IL-8 expression in hepatocytes. Silencing IGFBP-3 in Huh7 cells enhanced JNK and NF-κB activity and increased palmitate-induced IL-8 secretion. These data indicate that IGFBP-3 serves as an anti-inflammatory brake in hepatocytes against JNK and NF-κB and limits their activation and downstream production of proinflammatory cytokines. Under lipotoxic conditions, palmitate inhibits hepatic macrophage secretion of IGFBP-3, thereby releasing the brake and enhancing palmitate-induced IL-8 synthesis and secretion.-Min, H.-K., Maruyama, H., Jang, B. K., Shimada, M., Mirshahi, F., Ren, S., Oh, Y., Puri, P., Sanyal, A. J. Suppression of IGF binding protein-3 by palmitate promotes hepatic inflammatory responses.

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Section: Resultsmentioning

confidence: 99%

Suppression of IGF binding protein‐3 by palmitate promotes hepatic inflammatory responses

et al. 2016

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“…A study performed by Cha et al 62 showed that CD68 can serve as a receptor for binding malaria sporozoite, which promotes subsequent infection of resident hepatic macrophages. Data obtained by Song et al 54 indicate a lack of any involvement of macrosialin/CD68 in inflammatory responses to bacterial/viral pathogens and innate/ humoral immunity.…”

Section: Cd68: a Role In Inflammation And Immunitymentioning

confidence: 99%

CD68/macrosialin: not just a histochemical marker

Chistiakov

Killingsworth

Myasoedova

et al. 2017

Laboratory Investigation

497

330

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CD68 is a heavily glycosylated glycoprotein that is highly expressed in macrophages and other mononuclear phagocytes. Traditionally, CD68 is exploited as a valuable cytochemical marker to immunostain monocyte/macrophages in the histochemical analysis of inflamed tissues, tumor tissues, and other immunohistopathological applications. CD68 alone or in combination with other cell markers of tumor-associated macrophages showed a good predictive value as a prognostic marker of survival in cancer patients. Lowression of CD68 was found in the lymphoid cells, non-hematopoietic cells (fibroblasts, endothelial cells, etc), and tumor cells. Cell-specific CD68 expression and differentiated expression levels are determined by the complex interplay between transcription factors, regulatory transcriptional elements, and epigenetic factors. Human CD68 and its mouse ortholog macrosialin belong to the family of LAMP proteins located in the lysosomal membrane and share many structural similarities such as the presence of the LAMP-like domain. Except for a second LAMP-like domain present in LAMPs, CD68/microsialin has a highly glycosylated mucin-like domain involved in ligand binding. CD68 has been shown to bind oxLDL, phosphatidylserine, apoptotic cells and serve as a receptor for malaria sporozoite in liver infection. CD68 is mainly located in the endosomal/lysosomal compartment but can rapidly shuttle to the cell surface. However, the role of CD68 as a scavenger receptor remains to be confirmed. It seems that CD68 is not involved in binding bacterial/viral pathogens, innate, inflammatory or humoral immune responses, although it may potentially be involved in antigen processing/presentation. CD68 could be functionally important in osteoclasts since its deletion leads to reduced bone resorption capacity. The role of CD68 in atherosclerosis is contradictory.

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“…In this manner, the tetraspanin CD81, a surface molecule on hepatocytes and one of the main receptors for HCV , was identified as a crucial host factor for hepatocyte invasion of both, P. falciparum and P. yoelii sporozoites . Similarly, Cha and coworkers determined a critical role of host CD68 as a putative receptor for sporozoite invasion and traversal of Kupffer cells . A final relevant example is the host protein L‐FABP (liver‐fatty acid‐binding protein) that was found to specifically interact with the PV membrane‐resident protein, UIS3 (up‐regulated in sporozoites 3, ) within the infected hepatocyte, and which is presumably required for fatty acid uptake into the parasite .…”

Section: Wanted Ex or In Vivo—host Factors Involved In Intrahepatic Pmentioning

confidence: 99%

Plasmodium meets AAV—the (un)likely marriage of parasitology and virology, and how to make the match

et al. 2016

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The increasing use of screening technologies in malaria research has substantially expanded our knowledge on cellular factors hijacked by the Plasmodium parasite in the infected host, including those that participate in the clinically silent liver stage. This rapid gain in our understanding of the hepatic interaction partners now requires a means to validate and further disentangle parasite-host networks in physiologically relevant liver model systems. Here, we outline seminal work that contributed to our present knowledge on the intrahepatic Plasmodium host factors, followed by a discussion of surrogate models of mammalian livers or hepatocytes. We finally describe how Adeno-associated viruses could be engineered and used as hepatotropic tools to dissect Plasmodium-host interactions, and to deliberately control these networks for antimalaria vaccination or therapy.

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CD68 acts as a major gateway for malaria sporozoite liver infection

Abstract: Cha et al. use a phage display library screen to identify a peptide, P39, that binds to CD68 on the surface of Kupffer cells to inhibit malaria sporozoite cell entry. Thus, P39 may represent a therapeutic strategy for malaria by limiting hepatic infection.

Cited by 52 publications

References 40 publications

Suppression of IGF binding protein‐3 by palmitate promotes hepatic inflammatory responses

Suppression of IGF binding protein‐3 by palmitate promotes hepatic inflammatory responses

CD68/macrosialin: not just a histochemical marker

Plasmodium meets AAV—the (un)likely marriage of parasitology and virology, and how to make the match

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