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Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha.

Abstract Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogranulomatous inflammation that drives host pathology during chronic schistosomiasis. To address such controversy on the role of IL-4Rα, we generated a novel inducible IL-4Rα-deficient mouse model that allows for temporal knockdown of il-4rα gene after oral administration of Tamoxifen. Interrupting IL-4Rα mediated signaling during the acute phase impaired the development of protective type-2 immune responses, leading to rapid weight loss and premature death, confirming a protective role of IL-4Rα during acute schistosomiasis. Conversely, IL-4Rα removal at the chronic phase of schistosomiasis ameliorated the pathological fibro-granulomatous pathology and reversed liver scarification without affecting the host fitness. This amelioration of the morbidity was accompanied by a reduced Th2 response and increased frequencies of FoxP3+ Tregs and CD1dhiCD5+ Bregs. Collectively, these data demonstrate that IL-4Rα mediated signaling has two opposing functions during experimental schistosomiasis depending on the stage of advancement of the disease and indicate that interrupting IL-4Rα mediated signaling is a viable therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases like chronic schistosomiasis.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos neglected tropical diseases
Publication Year Start




PMID- 28827803
OWN - NLM
STAT- Publisher
DA  - 20170822
LR  - 20170822
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Linking)
VI  - 11
IP  - 8
DP  - 2017 Aug 21
TI  - Host regulation of liver fibroproliferative pathology during experimental
      schistosomiasis via interleukin-4 receptor alpha.
PG  - e0005861
LID - 10.1371/journal.pntd.0005861 [doi]
AB  - Interleukin-4 receptor (IL-4Ralpha) is critical for the initiation of type-2
      immune responses and implicated in the pathogenesis of experimental
      schistosomiasis. IL-4Ralpha mediated type-2 responses are critical for the
      control of pathology during acute schistosomiasis. However, type-2 responses
      tightly associate with fibrogranulomatous inflammation that drives host pathology
      during chronic schistosomiasis. To address such controversy on the role of
      IL-4Ralpha, we generated a novel inducible IL-4Ralpha-deficient mouse model that 
      allows for temporal knockdown of il-4ralpha gene after oral administration of
      Tamoxifen. Interrupting IL-4Ralpha mediated signaling during the acute phase
      impaired the development of protective type-2 immune responses, leading to rapid 
      weight loss and premature death, confirming a protective role of IL-4Ralpha
      during acute schistosomiasis. Conversely, IL-4Ralpha removal at the chronic phase
      of schistosomiasis ameliorated the pathological fibro-granulomatous pathology and
      reversed liver scarification without affecting the host fitness. This
      amelioration of the morbidity was accompanied by a reduced Th2 response and
      increased frequencies of FoxP3+ Tregs and CD1dhiCD5+ Bregs. Collectively, these
      data demonstrate that IL-4Ralpha mediated signaling has two opposing functions
      during experimental schistosomiasis depending on the stage of advancement of the 
      disease and indicate that interrupting IL-4Ralpha mediated signaling is a viable 
      therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases
      like chronic schistosomiasis.
FAU - Nono, Justin Komguep
AU  - Nono JK
AUID- ORCID: http://orcid.org/0000-0001-6153-9729
AD  - Cytokines and Diseases Group, International Centre for Genetic Engineering and
      Biotechnology, Cape Town Component, Cape Town, South Africa.
AD  - Division of Immunology, Health Science Faculty, University of Cape Town &
      Immunology of Infectious Disease Research Unit, South African Medical Research
      Council (SAMRC), Cape Town, South Africa.
AD  - The Medical Research Centre, Institute of Medical Research and Medicinal Plant
      Studies (IMPM), Ministry of Scientific Research and Innovation, Yaounde,
      Cameroon.
FAU - Ndlovu, Hlumani
AU  - Ndlovu H
AD  - Cytokines and Diseases Group, International Centre for Genetic Engineering and
      Biotechnology, Cape Town Component, Cape Town, South Africa.
AD  - Division of Immunology, Health Science Faculty, University of Cape Town &
      Immunology of Infectious Disease Research Unit, South African Medical Research
      Council (SAMRC), Cape Town, South Africa.
AD  - Department of Integrative Biomedical Sciences, Health Sciences Faculty,
      University of Cape Town, Cape Town, South Africa.
FAU - Abdel Aziz, Nada
AU  - Abdel Aziz N
AD  - Cytokines and Diseases Group, International Centre for Genetic Engineering and
      Biotechnology, Cape Town Component, Cape Town, South Africa.
AD  - Division of Immunology, Health Science Faculty, University of Cape Town &
      Immunology of Infectious Disease Research Unit, South African Medical Research
      Council (SAMRC), Cape Town, South Africa.
AD  - Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.
FAU - Mpotje, Thabo
AU  - Mpotje T
AD  - Cytokines and Diseases Group, International Centre for Genetic Engineering and
      Biotechnology, Cape Town Component, Cape Town, South Africa.
AD  - Division of Immunology, Health Science Faculty, University of Cape Town &
      Immunology of Infectious Disease Research Unit, South African Medical Research
      Council (SAMRC), Cape Town, South Africa.
FAU - Hlaka, Lerato
AU  - Hlaka L
AD  - Cytokines and Diseases Group, International Centre for Genetic Engineering and
      Biotechnology, Cape Town Component, Cape Town, South Africa.
AD  - Division of Immunology, Health Science Faculty, University of Cape Town &
      Immunology of Infectious Disease Research Unit, South African Medical Research
      Council (SAMRC), Cape Town, South Africa.
FAU - Brombacher, Frank
AU  - Brombacher F
AUID- ORCID: http://orcid.org/0000-0001-8881-6781
AD  - Cytokines and Diseases Group, International Centre for Genetic Engineering and
      Biotechnology, Cape Town Component, Cape Town, South Africa.
AD  - Division of Immunology, Health Science Faculty, University of Cape Town &
      Immunology of Infectious Disease Research Unit, South African Medical Research
      Council (SAMRC), Cape Town, South Africa.
LA  - eng
PT  - Journal Article
DEP - 20170821
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
EDAT- 2017/08/23 06:00
MHDA- 2017/08/23 06:00
CRDT- 2017/08/23 06:00
PHST- 2017/01/31 [received]
PHST- 2017/08/07 [accepted]
AID - 10.1371/journal.pntd.0005861 [doi]
AID - PNTD-D-17-00144 [pii]
PST - aheadofprint
SO  - PLoS Negl Trop Dis. 2017 Aug 21;11(8):e0005861. doi:
      10.1371/journal.pntd.0005861.