Myeloid-specific HNRNPA2B1 deficiency disrupts macrophage function and in vivo responses

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Mechanisms of innate immune gene regulation by heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) are unclear.
• HNRNPA2B1 is an RNA-binding protein implicated in various cellular processes.

Purpose of the Study:

• To investigate the role of HNRNPA2B1 in myeloid cells during innate immune responses.
• To elucidate the molecular mechanisms by which HNRNPA2B1 influences immune gene expression and macrophage function.

Main Methods:

• Generated myeloid lineage-specific HNRNPA2B1-conditional knockout mice using LysMCre.
• Utilized an endotoxic shock model and Salmonella enterica infection model.
• Performed transcriptomics analysis of LPS-treated HNRNPA2B1-deficient macrophages ex vivo.
• Assessed macrophage surface receptor expression and responsiveness to Interferon-gamma (IFNG).

Main Results:

• HNRNPA2B1-deficient mice showed dampened inflammatory mediator expression in endotoxic shock.
• These mice exhibited impaired protective inflammatory responses and higher bacterial burdens during Salmonella infection.
• Transcriptomics revealed increased nonproductive isoforms of Interferon-regulated genes, including Interferon-gamma receptor (IFNGR), in deficient macrophages.
• HNRNPA2B1 deficiency led to lower IFNGR surface expression and dampened IFNG responsiveness.

Conclusions:

• HNRNPA2B1 is essential for optimal macrophage function, particularly in restricting intracellular bacterial growth.
• The study highlights a previously unrecognized role for RNA-binding proteins in orchestrating effective immune defenses.
• HNRNPA2B1 regulates innate immunity through modulation of Interferon-stimulated gene expression and macrophage responsiveness.