HBEGF ⁺ macrophages in rheumatoid arthritis induce fibroblast invasiveness

Abstract

Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor–dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions.

A pharmacological interactome platform for discovery of pain mechanisms and targets

“…A previously published scRNA-seq study of synovial tissue from RA and osteoarthritis (OA) patients identified 4 specific sub types of macrophages within the joints of patients with either of these diseases (Kuo et al, 2019). In order to find macrophage-driven interactions with human DRG neurons that are potentially responsible for promoting pain in RA, we contrasted the RA enriched macrophage cell-types with the OA enriched macrophage cell-types.…”

“…Synovial scRNA-seq from RA and OA patients Kuo et al (Kuo et al, 2019), identified cell-types involved in different types of arthritis from scRNAseq data of 940 human synovial CD14+ cells. One cluster was associated with Rheumatoid Arthritis (RA) samples when compared with Osteoarthritis (OA) samples (RA-enriched macrophages).…”

“…RNA sequencing (RNA-seq) experiments have defined tissue-wide and cell-specific transcriptomes for much of the body in both mice (Usoskin et al, 2015;Schaum et al, 2018;Zeisel et al, 2018) and humans (Mele et al, 2015;Ray et al, 2018). Cell profiling experiments on normal and diseased tissues have identified key molecular players in an increasing number of disease processes (Roy et al, 2018), including disorders with a strong pain component (Hockley et al, 2018;Kuo et al, 2019). However, these studies mostly focus on gene expression within a specific tissue or across cell types in a tissue and do not characterize how multiple tissues may interact to promote disease.…”

“…First, we used single cell RNA-seq (scRNA-seq) data from colon-innervating nociceptors in the mouse (Hockley et al, 2018) to illustrate how these neurons interact with normal and inflamed enteric glial cells (Delvalle et al, 2018). Second, we examined how human DRG (hDRG) neurons (Ray et al, 2018;North et al, 2019) interact with macrophages taken from the joints of people with rheumatoid arthritis (RA) (Kuo et al, 2019). Finally, we assessed how pancreatic cancer (Tomczak et al, 2015) drives pharmacological interactions with hDRG neurons that could reveal new targets to provide relief for this notoriously painful disease.…”

Dissecting the human immune system with single cell RNA sequencing technology

“…In addition, the excessive activated Mϕs can lead to some autoimmune diseases such as rheumatoid arthritis (RA) by secreting inflammatory cytokines . Recently, a CEL­Seq2 scRNA‐seq study on the spectrum of Mϕ phenotypes from the synovial tissue of RA patients revealed an inflammatory Mϕ population that highly expresses HBEGF is enriched in RA synovial, and treatments can suppress the generation of these Mϕs, hinting a new therapeutic method in RA …”