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IL-1? promotes liver inflammation and necrosis during blood-stage Plasmodium chabaudi malaria.

ABSTRACT: Malaria causes hepatic inflammation and damage, which contribute to disease severity. The pro-inflammatory cytokine interleukin (IL)-1? is released by non-hematopoietic or hematopoietic cells during liver injury. This study established the role of IL-1? in the liver pathology caused by blood-stage P. chabaudi malaria. During acute infection, hepatic inflammation and necrosis were accompanied by NLRP3 inflammasome-independent IL-1? production. Systemically, IL-1? deficiency attenuated weight loss and hypothermia but had minor effects on parasitemia control. In the liver, the absence of IL-1? reduced the number of TUNEL⁺ cells and necrotic lesions. This finding was associated with a lower inflammatory response, including TNF-? production. The main source of IL-1? in the liver of infected mice was inflammatory cells, particularly neutrophils. The implication of IL-1? in liver inflammation and necrosis caused by P. chabaudi infection, as well as in weight loss and hypothermia, opens up new perspectives for improving malaria outcomes by inhibiting IL-1 signaling.

SUBMITTER: de Menezes MN

PROVIDER: S-EPMC6527574 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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IL-1α promotes liver inflammation and necrosis during blood-stage Plasmodium chabaudi malaria.

de Menezes Maria Nogueira MN Salles Érika Machado ÉM Vieira Flávia F Amaral Eduardo Pinheiro EP Zuzarte-Luís Vanessa V Cassado Alexandra A Epiphanio Sabrina S Alvarez José Maria JM Alves-Filho José Carlos JC Mota Maria Manuel MM D'Império-Lima Maria Regina MR

Scientific reports 20190520 1

Malaria causes hepatic inflammation and damage, which contribute to disease severity. The pro-inflammatory cytokine interleukin (IL)-1α is released by non-hematopoietic or hematopoietic cells during liver injury. This study established the role of IL-1α in the liver pathology caused by blood-stage P. chabaudi malaria. During acute infection, hepatic inflammation and necrosis were accompanied by NLRP3 inflammasome-independent IL-1α production. Systemically, IL-1α deficiency attenuated weight loss ...[more]

PMID: 31110285

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Project description:The role of the liver for survival of blood-stage malaria is only fragmentary understood. In the experimental blood-stage malaria Plasmodium chabaudi, protective vaccination induces self-healing and, thus, survival of otherwise lethal infections. This study investigates the response of the liver, in terms of mRNA and lincRNA expression, to vaccination-induced self-healing infections and lethal P. chabaudi malaria at early patency on day 4 p.i., when parasitized erythrocytes begin to appear in peripheral blood. Using gene expression microarrays, 23 genes were identified to be induced in the liver by >10-fold at p<0.01. More than one third were genes involved in erythropoiesis, as e.g. Kel, Rhag, Ahsp, Ermap, Slc4a1, Cldn13 Gata1, and Gfi1b. Another group of >10-fold expressed genes contain genes involved in natural cytotoxicity, as those encoding the killer cell lectin-like like receptors Klrb1a, Klrc3, Klrd1, Ncr1 and the granzyme B encoding Gzmb. In addition, there were identified a series of genes involved in the control of cell cycle and mitosis, as Ccnb1, Cdc25c, Ckap2l expressed by >10-fold only in vaccination-protected mice, and 22 genes being at least 100% higher expressed in vaccination-protected mice than the corresponding genes significantly expressed in non-vaccinated mice. Furthermore, distinct lincRNA species were changed by >3-fold in livers of vaccination-protected mice, whereas lethal malaria induced different lincRNAs. Our data suggest that protective vaccination accelerates extramedullary erythropoiesis, generation of liver-resident cytotoxic cells, and regeneration from malaria-induced injuries in the liver at early patency, which may be critical for final survival of otherwise lethal blood-stage malaria of P. chabaudi. Mice: Balb/c mice breeded under specified pathogen-free conditions were delivered from central animal facilities of the University of Düsseldorf. The experiments were performed only with female mice aged 10-12 weeks. They were housed in plastic cages, received a standard diet (Woehrlin, Bad Salzuflen, Germany) and water ad libitum. This study was carried out in strict accordance with the German law on animal protection. The keeping of mice as well as the experimental protocol of the study were officially approved by the State-controlled Committee on the Ethics of Animal Experiments of the State Nordrhein-Westfalen, Germany, and were regularly controlled, without being previously announced, by the local authorities. All efforts were undertaken to minimize suffering of mice. P. chabaudi malaria infection: Blood-stage infections of P. chabaudi were kept in outbred mice under sterile conditions by weekly passages of infected blood. A non-clonal line of P. chabaudi is used in our laboratory since 1982, which resembles to P. chabaudi chabaudi. Challenge of Balb/c mice with 10^6 P. chabaudi-infected erythrocytes, Protective vaccination: As a vaccine, host cell plasma membranes were used, which were isolated in the form of ghosts from P. chabaudi-parasitized erythrocytes Approximately 10^6 ghosts were suspended in 100 µl Freund’s complete adjuvant (FCA) and subcutaneously injected on week 3 and week 1 before infecting with P. chabaudi-parasitized erythrocytes. Control mice were treated in parallel only FCA.

Dataset Information

IL-1? promotes liver inflammation and necrosis during blood-stage Plasmodium chabaudi malaria.

Publications

IL-1α promotes liver inflammation and necrosis during blood-stage Plasmodium chabaudi malaria.

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