What is the Role of Different Macrophage Subsets in the Evolution of Juvenile Xanthogranulomas?
Authors: Wegher Lissa S.M. , Kazmarek Laura M. , Silva Andressa C.F. , Maciel Marina G. , Sasso Bruna M. , Teixeira Fernanda , Cintra Maria L. 
Published: April 2022

There are several activated forms of macrophages: 2 main groups are designated M1 and M2. While M1 macrophages have proinflammatory, bactericidal, and phagocytic functions and are the dominant phenotype observed in the early stages of inflammation, M2 macrophages are involved in constructive processes such as tissue repair; they play a role in wound healing and are required for revascularization and re-epithelialization. Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis. Its pathogenesis is not well understood, but it is not considered a neoplastic entity. JXGs possibly appear as a reaction to a nonspecific injury such as trauma or viral infection, although a genetic predisposition has been suggested in some cases. Tissue damage leads to a histiocytic response. JXGs appear, evolve toward maturation, and then most of them spontaneously regress. Young JXGs are characterized by small macrophages scattered in the dermis, in apposition close to the epidermis. As the lesion matures, the number of foamy macrophages and Touton cells increases and other cell types such as plasma cells, lymphocytes, and polymorphs are observed. Regressing xanthogranulomas will show numerous spindle cells in Significant values are in bold.a storiform distribution, interstitial fibrosis, and few foamy and Touton cells. In this study, we studied the immunophenotypic profile of macrophages found in cutaneous JXGs according to their stage of maturation. We examined the skin biopsies from 25 patients; all were embedded in paraffin and stained with hematoxylin and eosin and for immunohistochemistry. Typically, all JXGs were positive for factor XIIIa and CD4, and were negative for CD1a. The following histiocyte markers were used: CD68, CD204, CD163, MAC387, and HAM56. Images were analyzed by Image J software; data were statistically evaluated by SAS 9.0 software. The cases showed a slight predominance of males and the preference of the JXGs for the axial skin. Lesions occupied the papillary and reticular dermis in 85% of the cases and extended to the subcutaneous fat in the remainder. Compared with mature and regressing JXGs, younger lesions had a higher density of M1 macrophages, stained with MAC387. This antibody labels the histiocytes that have recently arrived in the areas of inflammation. As the lesions matured, there was an overwhelming predominance of M2 macrophages. These cells tended to cluster against the epidermis, except in the 2 cases in phase of regression. This suggests that there is a cross-talk between the epidermis and macrophages and that receptors, cytokines, chemokines, and adhesion molecules may play a role in the development and evolution of JXGs. These results indicate that, for most of their life, JXGs are formed by repairing M2 macrophages and are not just an M1 macrophagic response to a local antigen. The process appears to be influenced by chemical-mediator epidermal-macrophage cross-talking, considering the tendency of these cells to accumulate against the dermoepidermal junction.