LPS and type I and II interferons have opposing effects on epigenetic regulation of LAIR1 expression in mouse and human macrophages

Inhibitory immune receptors are important for maintaining immune homeostasis. We identified epigenetic alterations in 2 members of this group, LAIR1 and LAIR2, in lymphoma patients with inflammatory tissue damage and susceptibility to infection. We predicted that the expression of LAIR genes is controlled by immune mediators acting on transcriptional regulatory elements. Using flow cytometry, quantitative reverse-transcription polymerase chain reaction, and RNA sequencing, we measured LAIR1 and LAIR2 in human and murine immune cell subsets at baseline and posttreatment with immune mediators, including type I and II interferons, tumor necrosis factor α, and lipopolysaccharide (LPS). We identified candidate regulatory elements using epigenome profiling and measured their regulatory activity using luciferase reporters. LAIR1 expression substantially increases during monocyte differentiation to macrophages in both species. In contrast, murine and human macrophages exhibited opposite changes in LAIR1 in response to immune stimuli: human LAIR1 increased with LPS while mouse LAIR1 increased with interferon γ. LAIR genes had distinct patterns of enhancer activity with variable responses to immune stimuli. To identify relevant transcription factors (TFs), we developed integrative bioinformatic techniques applied to TF chromatin immunoprecipitation sequencing, RNA sequencing, and luciferase activity, revealing distinct sets of TFs for each LAIR gene. Most strikingly, LAIR1 TFs include nuclear factor kappa B factors RELA and RELB, while Lair1 and LAIR2 instead include STAT3 and/or STAT5. Regulation by nuclear factor kappa B factors may therefore explain the LPS-induced increase in LAIR1 expression, in contrast to Lair1 decrease. Our findings reveal new insights into transcriptional mechanisms that control distinct expression patterns of LAIR genes in response to inflammatory stimuli in human and murine myeloid and lymphoid cells.