Differential expression of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) in tissue eosinophils

Abstract

No longer regarded simply as end‐stage cytotoxic effectors, eosinophils are now recognized as complex cells with unique phenotypes that develop in response stimuli in the local microenvironment. In our previous study, we documented eosinophil infiltration in damaged muscle characteristic of dystrophin‐deficient (mdx) mice that model Duchenne muscular dystrophy. Specifically, we found that eosinophils did not promote the generation of muscle lesions, as these persisted in eosinophil‐deficient mdx.PHIL mice. To obtain additional insight into these findings, we performed RNA sequencing of eosinophils isolated from muscle tissue of mdx, IL5tg, and mdx.IL5tg mice. We observed profound up‐regulation of classical effector proteins (major basic protein‐1, eosinophil peroxidase, and eosinophil‐associated ribonucleases) in eosinophils isolated from lesion‐free muscle from IL5tg mice. By contrast, we observed significant up‐regulation of tissue remodeling genes, including proteases, extracellular matrix components, collagen, and skeletal muscle precursors, as well as the immunomodulatory receptor, Trem2, in eosinophils isolated from skeletal muscle tissue from the dystrophin‐deficient mdx mice. Although the anti‐inflammatory properties of Trem2 have been described in the monocyte/macrophage lineage, no previous studies have documented its expression in eosinophils. We found that Trem2 was critical for full growth and differentiation of bone marrow‐derived eosinophil cultures and full expression of TLR4. Immunoreactive Trem2 was also detected on human peripheral blood eosinophils at levels that correlated with donor body mass index and total leukocyte count. Taken together, our findings provide important insight into the immunomodulatory and remodeling capacity of mouse eosinophils and the flexibility of their gene expression profiles in vivo.

Impact of controlled high-sucrose and high-fat diets on eosinophil recruitment and cytokine content in allergen-challenged mice

“…Rather than focusing on single mediators, we performed a global assessment of cytokines in the airways using a membrane-based array method that detects soluble mediators via a “sandwich” method analogous to that used by a standard ELISA. This method was featured in several earlier studies [ 20 , 25 , 28 ] including one in which we validated array findings in lysates of peripheral blood eosinophils isolated from ~40 independent donors with standard cytokine-specific ELISAs [ 25 ].…”

“…Although diet had no apparent impact on eosinophil recruitment to the airways, we performed experiments that would permit us to identify differences in eosinophil cytokine content. Several previous studies focused on eosinophil heterogeneity and the influence of the tissue microenvironment on eosinophil structure and contents [ 19 , 20 ]. Mice on defined diets (basic, high-fat, or high-sucrose) were challenged with Aa as shown in Fig 2A and eosinophils in lung tissue (live CD45 + CD11c - Gr1 lo MHCII - SiglecF + were isolated by FACS ( Fig 4A ).…”

“…[ 19 ] and Sek et al . [ 20 ] in studies focused on eosinophils associated with tumor tissue and muscle lesions, respectively.…”

“…Profiling of BAL fluid and eosinophil lysates was performed using the Mouse Cytokine Array Panel A (R & D Systems, Minneapolis, MN) as per manufacturer’s instructions and as previously described [ 20 , 28 ]. Briefly, combined samples (from n = 5 mice) were incubated with the Mouse Cytokine Array Panel A detection antibody cocktail for one hour at room temperature.…”

“…Similarly, a recent study by Sek et al . [ 20 ] revealed that eosinophils isolated from muscle tissue of mdx (muscular dystrophy) mice differentially expressed tissue remodeling genes and the immunomodulatory receptor, Trem2 . Likewise, Ma et al .…”