SPP1^hi macrophages, NKG7 T cells, CCL5^hi fibroblasts, and IgM plasma cells are dominant features of necrobiosis

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Abstract

Necrobiosis is a histologic term used to describe abnormal deposits of “degenerating” collagen within the skin. It can be found as an incidental finding in various granulomatous conditions, but is a hallmark of necrobiosis lipoidica (NL) and necrobiotic xanthogranuloma (NXG). There is limited prior research on necrobiosis. Here, we employed single-cell analysis of lesional and nonlesional skin to study the pathophysiology of necrobiosis. Our findings demonstrate that necrobiotic lesional skin is characterized by SPP1hi macrophages expressing MARCO; NKG7-expressing effector CD8+ T cells coexpressing CCL5, IFNG, GZMs, and PRF1; CCL5hi fibroblasts coexpressing CXCL9, diverse collagens (e.g., COL4A4, COL11A1, COL8A1), and TIMP1; and IGHM-expressing plasma cells. Integrative analysis of signaling ligands and receptor expression identified strong cell-cell communication between NKG7+ T cells, CCL5hi fibroblasts, and SPP1-expressing macrophages. In contrast, these cell populations were not dominant features of systemic sclerosis, another collagen deposition disease. Furthermore, although SPP1-expressing macrophages were detectable in sarcoidosis, IFNG-expressing T cells were a more defining feature of sarcoidosis compared with NL and NXG. From these findings, we speculate that necrobiosis results from the deposition of diverse collagens and ECM proteins through a process driven by CCL5-expressing fibroblasts and SPP1-expressing macrophages.

Authors

Stephanie T. Le, Alina I. Marusina, Alexander A. Merleev, Amanda Kirane, Olga Kruglinskaya, Andrey Kunitsyn, Nikolay Yu Kuzminykh, Xianying Xing, Sophie Y. Li, William Liakos, J. Michelle Kahlenberg, Andrea Gompers, Lauren Downing, Sahiti Marella, Allison C. Billi, Paul W. Harms, Lam C. Tsoi, Marie-Charlotte Brüggen, Iannis E. Adamopoulos, Johann E. Gudjonsson, Emanual Maverakis