A microarray window into granulocyte development and function

Comment on Theilgaard-Mönch et al, page 1785

This study provides a detailed analysis of gene expression patterns during granulocytic maturation and in so doing provides novel insights into myeloid cell development and activities.

As part of the innate immune system, granulocytes are essential for host defense against invading microorganisms. Theilgaard-Mönch and colleagues have applied microarray analysis to uncover the weapons these short-lived cells bring to this task and the complex program that allows neutrophils to develop from immature myeloblasts. Density gradient centrifugation followed by immunodepletion of other lineages allowed purification of myeloblast/promyelocyte (PM), myelocyte/metamyelocyte (MY), and band cell/polymorphonuclear leukocyte (bm-PMN) populations from human marrow and of a pb-PMN population from human peripheral blood.

A variety of RNAs encoding regulatory receptors were identified in PMNs, including interferon, interleukin, chemokine, and tumor necrosis factor receptors and members of the leukocyte immunoglobulin (Ig)–like receptor family also present in monocytes. Receptors that recognize microorganisms directly or through antibody intermediates were also up-regulated as were cytokines and chemokines that may allow autocrine control. In addition, novel secondary granule proteins, such as galectin-3 and its receptors, haptoglobin, and several protease inhibitors were uncovered. These new insights into expression of proteins that control and effect granulocyte functions in defense against a spectrum of microorganisms will enable future studies to understand and even improve innate immunity.FIG1 

Granulocytes are born to die, perhaps as a means of protecting the host against their toxic contents. While p53 was down-regulated in granulocytes, histone H1.2, an inducer of apoptosis, increased as did death receptors and their ligands and several proapoptotic BH3-only proteins. The roles of each of these molecules in neutrophil survival also bear further investigation.

The microarray data obtained should also assist investigations focused on the transcriptional program mediating the development of granulocytes from myeloblasts. While the roles of CCAAT/enhancer-binding protein-α (C/EBPα), C/EBPϵ, PU.1, retinoic acid receptor α (RARα), CCAAT displacement protein (CDP), and several other factors have been described,¹  additional transcription factors, coactivators, corepressors, and histone-modifying and remodeling proteins are likely involved. Cell-cycle inhibition mediated by interaction of C/EBPs with E2 promoter binding factor (E2F) may also facilitate terminal maturation,^2,3  and indeed the array data demonstrate down-regulation of multiple E2F genetic targets during the promyelocyte to myelocyte transition. ▪