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

Abstract

The mechanisms through which heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) contributes to innate immune gene regulation are poorly understood. To fill this gap, we generated a myeloid lineage-specific HNRNPA2B1-conditional mouse using LysMCre. In an endotoxic shock model, HNRNPA2B1-deficient mice exhibit dampened expression of inflammatory mediators despite increased infiltration of macrophages and neutrophils. Likewise, during infection with the gram-negative bacterial pathogen Salmonella enterica, HNRNPA2B1-deficient mice fail to mount protective inflammatory responses and experience higher bacterial burdens. To better understand the molecular mechanisms driving these phenotypes in vivo, we performed transcriptomics analysis of LPS-treated HNRNPA2B1-deficient macrophages ex vivo. We noted an increase in transcripts encoding nonproductive isoforms of a number of Interferon (IFN)-regulated genes, including the IFNG receptor (IFNGR). Focusing on IFNGR, we confirmed lower surface expression on HNRNPA2B1-deficient macrophages and dampened responsiveness in response to IFNG treatment. In conclusion, our data demonstrates that HNRNPA2B1 is essential for optimal macrophage function, particularly in the context of intracellular bacterial restriction in the case of Salmonella infection. This highlights a previously unappreciated role for RNA-binding proteins in mounting effective immune defenses.