E-cadherin is expressed by mono- and multinucleated histiocytes in cutaneous sarcoidal and foreign body granulomas

Abstract

E-cadherin, a member of the cadherin family of transmembrane adhesion receptors, is critical for cutaneous barrier function, as it promotes keratinocyte and Langerhans cell adhesion in the epidermis. Recent murine models of chronic inflammation identified new E-cadherin expressing subsets of mononuclear phagocytes, including alternatively activated macrophages and selected inflammatory dendritic cells. It has been shown in vitro that expression of E-cadherin by murine macrophages promotes their homotypic aggregation and fusion to multinucleated giant cells (MNGCs), a signature cell type of granulomatous inflammation. The purpose of this study was to assess E-cadherin expression on histiocytes and giant cells in cutaneous granulomas in humans. E-cadherin expression was evaluated by immunohistochemistry of formalin-fixed paraffin-embedded skin biopsies of foreign body granulomas (n = 21) and sarcoidosis (n = 21). The results showed consistent membranous E-cadherin staining pattern on mononucleated histiocytes and MNGCs in both granuloma types. These E-cadherin expressing histiocytes are distinct from dermal Langerhans cells because they lacked CD1a expression. Our findings suggest that E-cadherin expressing mononuclear histiocytes are likely precursors for MNGCs in cutaneous granulomas and may play a critical role in disease pathogenesis.

Figure 1

E-cadherin staining of foreign body granulomas. Hematoxylin and eosin (H&E) stained sections demonstrated FBGR at sites of follicular cyst rupture (A, 100x magnification, and B, 600x magnification). Immunohistochemical staining for E-cadherin demonstrated specific membranous staining on granuloma-associated histiocytes and MNGCs on low power (100x magnification) (C, E, G and I) and high power magnification (600x) (D, F, H and J). ). Foreign body reactions were to site of follicular rupture (A–D, G–H) and granulomatous reaction to scar (E–F, I–J).

Figure 2

E-cadherin staining of cutaneous sarcoidosis. Hematoxylin and eosin (H&E) stained sections demonstrated naked granulomas composed of epithelioid histiocytes and MNGCs (A and B). E-cadherin staining pattern of mononuclear and multinuclear histiocytes demonstrated membranous staining. Low power magnification, 100x (C, E, G, and I) and high power magnification, 600x (2D, F, H and J).

Figure 3

Potential immune function of E-cadherin⁺ histiocytes in foreign body and sarcoidal granulomas. (A) IL-4/IL-13 promotes the differentiation of E-cadherin⁺ AAMacs from E-cadherin⁻ monocytic precursors. Fusion of E-cadherin⁺ AAMacs results in MNGC formation. (B) Presumed potentiation of TH1 and TH17 responses in sarcoidosis by E-cadherin⁺ AADCs and IL-23-producing inflammatory DCs, respectively. IFN-γ and IL-17A promote the fusion of E-cadherin⁺ mononuclear precursors to form E-cadherin⁺ MNGCs.