Identification of Nuclear Matrix Protein 4 (Nmp4) as a novel regulator of innate immunity

Abstract

Abstract Mesenchymal stem/progenitor cells (MSPCs) have immunomodulatory activity. We previously observed that osteoprogenitors and CD8+T cells are increased in the bone marrow (BM) of mice lacking the transcription factor Nmp4. Transcriptome analysis of MSPCs from Nmp4−/− and wild type (WT) mice revealed significant changes in genes related to innate immune responses, including reduced expression of Tlr3 and Mda5 in the null MSPCs. Loss of Nmp4 increased mRNA translation, ribosomal biogenesis, and Gadd34 expression in MSPCs; collectively, these processes likely promote the unfolded protein response (UPR), expanding the processing capacity of the endoplasmic reticulum. Therefore, we hypothesized that disabling Nmp4 would improve innate immune cell function. To test this, Nmp4−/− mice (C57BL6) were infected intranasally with influenza A/PR8 (H1N1; 150pfu). Despite having similar virus load in the lung, H1N1-infected Nmp4−/− mice lost less body weight than WT mice post infection and had improved survival. Infected Nmp4−/− mice had fewer infiltrating neutrophils (PMNs; CD11b+/Ly6G+) and monocytes (CD11b+/SiglecFNeg/Ly6GNeg/Ly6C+) in bronchoalveolar lavage (BAL) but more BAL macrophages (CD11c+/SiglecF+); CD4+ and CD8+ T cells were not different between genotypes. Ex vivo, Nmp4-deficiency did not alter the differentiation of BM marrow-derived macrophages; however, Chil3/Ym1 and Alox15 mRNA expression was reduced in Nmp4−/− macrophages polarized with IL-4/IL-13, suggesting cell-autonomous regulation of M2 macrophage activation by Nmp4. Our data point to Nmp4 as a novel regulator of innate immunity and influenza response in mice.