Interferon-sensitized hematopoietic progenitors dynamically alter organismal immunity

Area of Science:

• Immunology
• Hematopoiesis
• Inflammation Biology

Background:

• Tissue-restricted inflammation can profoundly influence systemic immunity.
• The specific mechanisms linking localized inflammation to systemic immune alterations remain incompletely understood.
• Hematopoietic stem/progenitor cells (HSPCs) are central to immune responses, but their modulation by peripheral signals is an active area of research.

Purpose of the Study:

• To elucidate the mechanisms by which tissue-restricted inflammation reprograms systemic host responses.
• To investigate the role of type I interferon (IFN) signaling in modulating hematopoietic stem/progenitor cells (HSPCs) following inflammation.
• To determine the functional consequences of IFN-mediated HSPC alterations on host immunity.

Main Methods:

• Utilized a compartmentalized model of skin inflammation in mice.
• Analyzed systemic immune responses, including protection from atherosclerosis and outcomes of influenza virus infection.
• Investigated the role of IFNAR signaling and employed recombinant IFNα administration.
• Performed HSPC transfer experiments to assess the heritability of immune phenotypes.
• Examined long-term changes in chromatin accessibility and progenitor cell states.

Main Results:

• Skin inflammation induced type I IFN-mediated activation of HSPCs, leading to significant systemic immune changes.
• Post-inflamed mice exhibited protection from atherosclerosis but increased susceptibility to influenza infection.
• IFNAR signaling was critical for IFN-mediated HSPC modulation, which could be mimicked by IFNα administration.
• Adoptive transfer of post-inflamed HSPCs successfully transmitted the immune suppression phenotype.
• IFN-induced alterations in HSPCs involved lasting epigenetic changes and the development of an IFN-responsive state.

Conclusions:

• Transient inflammation, particularly type I IFN signaling, exerts enduring effects on HSPC function and systemic immunity.
• IFN-modulated HSPCs can program distinct systemic immune outcomes, including altered susceptibility to distinct diseases.
• These findings reveal a novel pathway for peripheral immune signals to shape long-term hematopoietic stem cell function and host defense.