Cascade of Inflammatory, Fibrotic Processes, and Stress-Induced Senescence in Chronic GVHD-Related Dry Eye Disease

Abstract

Ocular graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Ocular GVHD affects recipients' visual function and quality of life. Recent advanced research in this area has gradually attracted attention from a wide range of physicians and ophthalmologists. This review highlights the mechanism of immune processes and the molecular mechanism, including several inflammation cascades, pathogenic fibrosis, and stress-induced senescence related to ocular GVHD, in basic spectrum topics in this area. How the disease develops and what kinds of cells participate in ocular GVHD are discussed. Although the classical immune process is a main pathological pathway in this disease, senescence-associated changes in immune cells and stem cells may also drive this disease. The DNA damage response, p16/p21, and the expression of markers associated with the senescence-associated secretory phenotype (SASP) are seen in ocular tissue in GVHD. Macrophages, T cells, and mesenchymal cells from donors or recipients that increasingly infiltrate the ocular surface serve as the source of increased secretion of IL-6, which is a major SASP driver. Agents capable of reversing the changes, including senolytic reagents or those that can suppress the SASP seen in GVHD, provide new potential targets for the treatment of GVHD. Creating innovative therapies for ocular GVHD is necessary to treat this intractable ocular disease.

Keywords: dry eye disease; graft-versus-host disease; molecular mechanism; stress-induced senescence.

Figure 1

A variety of biological areas orchestrate in ocular GVHD, dry eye disease, which are representative of a manifestation of ocular GVHD and are related to various aspects of the study area including the tear film, microbiome, mucosal and exocrine gland immunity, stem cell biology on HSC or MSCs, acute and chronic inflammation, pathogenic fibrosis including fibroblasts origin, and stress-induced senescence. Those pathways are connected timely and spatially to each other and the development of ocular GVHD, MSC; mesenchymal stem cells, HSC; hematopoietic stem cells, EMT; epithelial mesenchymal transition.

Figure 2

Migration of senescent macrophages play a key role in ocular GVHD. A pro-inflammatory state related to the conditioning regimen, and previous acute GVHD, may lead to an accumulation of cell debris, resulting in the activation of RAS, ER stress, oxidative stress, and senescent cell involving SASP accumulation on the ocular surface and in the lacrimal gland. 8-OHdG; 8-hydroxy-2′-deoxyguanosine, 4-HNE; 4-hydroxy-2-nonenal, HEL; hexonoyl lesion, IL-6, interleukine-6, CXCL9; C-X-C motif ligand 9, OPN; osteopontin, CD; clustered of differentiation.