VSIG4(+) peritoneal macrophages induce apoptosis of double-positive thymocyte via the secretion of TNF-\u03b1 in a CLP-induced sepsis model resulting in thymic atrophy

Hae-Yun Cho,Yun Gyeong Yang,Inhak Choi,Chae-Kwan Lee,Youkyoung Jeon,Soo-Woong Lee

doi:10.1038/s41419-021-03806-5

Abstract

Thymic atrophy in sepsis is a critical disadvantage because it induces immunosuppression and increases the mortality rate as the disease progresses. However, the exact mechanism of thymic atrophy has not been fully elucidated. In this study, we discovered a novel role for VSIG4-positive peritoneal macrophages (V4(+) cells) as the principal cells that induce thymic atrophy and thymocyte apoptosis. In CLP-induced mice, V4(+) cells were activated after ingestion of invading microbes, and the majority of these cells migrated into the thymus. Furthermore, these cells underwent a phenotypic shift from V4(+) to V4(−) and from MHC II(low) to MHC II(+). In coculture with thymocytes, V4(+) cells mainly induced apoptosis in DP thymocytes via the secretion of TNF-α. However, there was little effect on CD4 or CD8 SP and DN thymocytes. V4(−) cells showed low levels of activity compared to V4(+) cells. Thymic atrophy in CLP-induced V4(KO) mice was much less severe than that in CLP-induced wild-type mice. In addition, V4(KO) peritoneal macrophages also showed similar activity to V4(−) cells. Taken together, the current study demonstrates that V4(+) cells play important roles in inducing immunosuppression via thymic atrophy in the context of severe infection. These data also suggest that controlling the function of V4(+) cells may play a crucial role in the development of new therapies to prevent thymocyte apoptosis in sepsis.

Highlights

Sepsis is a major cause of death and is associated with high rates of mortality and morbidity worldwide[1]
Peritoneal macrophages were found in the thymus after cecal ligation and puncture (CLP) induction
As known previously, when sepsis was induced by CLP in mice, we found that the thymus becomes atrophy as sepsis progresses (Fig. 1a)

Summary

Introduction

Sepsis is a major cause of death and is associated with high rates of mortality and morbidity worldwide[1]. 750,000 cases are reported in the United States annually, and the mortality rate is as high as 28–50%2. Sepsis occurs as an early inflammatory response to infection, and patients with sepsis are often immunosuppressed. Extensive and profound immune cell apoptosis can be induced in multiple experimental animal models and has been shown in human studies[3,4]. The thymus is the primary lymphoid organ in which bone marrow-derived T-cell precursors develop into mature T cells. Thymocyte maturation depends on essential signals produced by dendritic cells, macrophages, endothelial cells, fibroblasts, and thymic epithelial cells that surround immature thymocytes[8]. Thymocyte fate during differentiation is decided according to interactions with

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Conclusion