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Type-I IFN signaling suppresses an excessive IFN-gamma response and thus prevents lung damage and chronic inflammation during Pneumocystis (PC) clearance in CD4 T cell-competent mice.

eagle-i ID

http://montana.eagle-i.net/i/0000012f-941b-1188-b822-788380000000

Resource Type

  1. Journal article

Properties

  1. Resource Description
    Immune-reconstitution after highly active antiretroviral therapy (HAART) is often incomplete, and some HIV-infected individuals fail to regenerate type-I interferon (IFN)-producing pDCs. We recently demonstrated that during Pneumocystis (PC) infection in CD4 T cell-competent mice the absence of type-I IFN signaling results in chronic pulmonary inflammation and fibrosis despite clearance. Because the mechanisms involved are poorly understood, we further characterized the role of type-I IFN signaling in immune responses to PC. We show that type-I IFN signaling around day 7 postinfection is critical to the outcome of inflammation. Microarray analysis of pulmonary CD11c(+) cells revealed that at day 7 post infection, wild-type cells up-regulated type-I IFN-responsive genes as well as SOCS1, which is a critical negative-regulator of type-I IFN and IFN-gamma signaling. This was associated with an eosinophilic lung inflammation, PC clearance, and complete restitution. However, pulmonary CD11c(+) cells from IFNAR(-/-) mice demonstrated increased tumor necrosis factor (TNF)-alpha production and lacked SOCS1-induction at day 7. This was followed by a transient lymphocytic and IFN-gamma response before switching to a chronic eosinophilic inflammation of the lung. Early neutralization of TNF-alpha did not prevent chronic inflammation in IFNAR(-/-) mice, but treatment with an anti-IFN-gamma antibody did. We propose that during PC lung infection type-I IFNs induce SOCS1-associated regulatory mechanisms, which prevent excessive IFN-gamma-mediated responses that cause chronic lung damage. Therefore, partial immune-reconstitution in AIDS, attributable to reduced type-I IFN actions, might disrupt regulatory aspects of inflammation, causing unexplained chronic pulmonary complications as seen in some patients during HAART.
  2. Author
    Harmsen, Allen, Ph.D.
  3. Website(s)
    http://www.ncbi.nlm.nih.gov/pubmed/20395428
  4. PubMed ID
    20395428
 
RDFRDF
 
Provenance Metadata About This Resource Record
  1. workflow state
    Published
  2. contributor
    qking (Quinton King)
  3. created
    2011-04-26T18:18:34.524-05:00
  4. creator
    qking (Quinton King)
  5. modified
    2011-04-26T18:19:15.641-05:00

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