Atypical monocytes conspire with nuclear exosomes to promote organ fibrosis

Abstract

Li discusses the discovery of novel mechanisms and pathways involving atypical monocytes and nuclear paraspeckles in organ fibrosis. Li discusses the discovery of novel mechanisms and pathways involving atypical monocytes and nuclear paraspeckles in organ fibrosis. CITATIONS Fukushima K, Satoh T, Sugihara F, et al. Dysregulated expression of the nuclear exosome targeting complex component Rbm7 in non-hematopoietic cells licenses the development of fibrosis. Immunity. 2020;52:542–556. Satoh T, Nakagawa K, Sugihara F, et al. Identification of atypical monocyte and committed progenitor involved in fibrosis. Nature. 2017;541:96–101. Fibrosis is a significant topic in transplantation. It is the final presentation of a plethora of chronic diseases, including chronic rejection, and we do not have an effective therapy. The Akira group in Japan reported the discovery of a unique monocytic cell type in tissue fibrosis called segregated-nucleus–containing atypical monocytes (SatMs; Satoh et al). The group recently described exciting new molecular mechanisms involving nuclear exosomes and the death of parenchymal cells in the recruitment of SatMs to fibrotic organs (Fukushima et al). These findings are of great interest to the field of organ transplantation, especially in tackling some of the key problems in chronic rejection. The authors used a chemically induced lung fibrosis model in mice, in which the intratracheal injection of bleomycin led to excessive lung inflammation in the first week due to airway epithelial injury, followed by the development of prominent lung fibrosis. In this model, the authors showed that the inflammatory and fibrotic responses are two separate events involving distinct mechanisms and cell types and that SatMs exclusively mediate the fibrotic response. The authors provided compelling evidence that SatMs represent a unique cell type different from any other myeloid cell types. Phenotypically, SatMs are identified as Ceacam1+/Msr1+/Mac1+/Ly6C–/F4/80– cells, and, functionally, they are superb activators of tissue fibroblasts (producers of matrix proteins). They possess a bilobed and segmented nucleus and have ample cytoplasmic granules, showing a transcriptional profile that straddles that of monocytes and granulocytes. They depend entirely on the transcription factor CCAAT enhancer binding protein beta (C/EBPβ) for development, as genetic knockout of C/EBPβ (i.e., Cebpb–/– mice) selectively abolished SatMs. Importantly, Cebpb–/– mice are highly resistant to the induction of lung fibrosis, although the inflammatory response in the lungs is not perturbed, demonstrating that SatMs are necessary and sufficient in promoting tissue fibrosis in vivo. In pursuing the mechanisms that account for the selective recruitment of SatMs to fibrotic lesions, the authors meticulously designed and carefully executed a series of elegant experiments using state-of-the-art sequencing and molecular tools. These led to the discovery of an RNA-binding protein called RNA-binding motif protein 7 (or Rbm7), as well as a detailed revelation of how Rbm7 works in vivo in promoting fibrosis. The authors showed that Rbm7 is expressed in nonhematopoietic cells in the lungs, especially in airway epithelial cells. Moreover, Rbm7 expression is inducible, especially in response to injury inflicted by bleomycin, and is confined to areas of fibrosis and associated with SatM recruitment. Additionally, genetic knockout of Rbm7, similar to C/EBPβ knockout, prevented the induction of fibrosis by bleomycin. The mechanistic aspect of the pursuit was really creative and novel. The authors presented extensive data showing that, in response to injury, the airway epithelial cells assemble nuclear exomes, also called paraspeckles. The long noncoding (lnc)RNA (i.e., nuclear paraspeckle assembly transcript [NEAT]1/2) serves as a scaffold to bring together DNA repair molecules (e.g., breast cancer [BRCA]1) to form nuclear paraspeckles. As a consequence of cellular stress responses, such paraspeckles are critical in repairing DNA damage and preventing epithelial cell death. Interestingly, once induced, Rbm7 preferentially binds the lncRNA, resulting in the degradation of lncRNA and the subsequent dismantling of the paraspeckles. This renders the airway epithelial cells extremely sensitive to DNA damage and cell death, and the death of epithelial cells then releases the chemokine CXCL12, which acts as a potent chemoattractant to SatMs. Thus, these experiments identify Rbm7 as a critical regulator of tissue fibrosis. The authors extended their findings to include human fibrotic samples (fibrotic kidney, liver and lungs), showing that similar mechanisms may also be operative in tissue fibrosis in humans. Clearly, these studies may open the door to the development of new strategies and therapeutics specifically targeting organ fibrosis, which is an area of tremendous importance in transplantation. Xian C. Li, MD, PhD, is a professor and director at the Immunobiology and Transplant Science Center and Department of Surgery at Houston Methodist Hospital. He is also section editor of “Literature Watch.”