M. leprae interacts with the human epidermal keratinocytes, neonatal (HEKn) via the binding of laminin-5 with α-dystroglycan, integrin-β1, or -β4

Abstract

Although Mycobacterium leprae ( M . leprae ) is usually found in macrophages and nerves of the dermis of patients with multibacillary leprosy, it is also present in all layers of the epidermis, basal, suprabasal, prickle cells, and keratin layers. However, the mechanism by which M . leprae invades the dermis remains unknown, whereas the underlying mechanism by which M . leprae invades peripheral nerves, especially Schwann cells, is well defined. M . leprae binds to the α-dystroglycan (DG) of Schwann cells via the interaction of α-DG and laminin (LN) -α2 in the basal lamina, thus permitting it to become attached to and invade peripheral nerves. In the current study, we investigated the issue of how M . leprae is phagocytosed by human epidermal keratinocytes, neonatal (HEKn). LN-5 is the predominant form of laminin in the epidermis and allows the epidermis to be stably attached to the dermis via its interaction with α/β-DG as well as integrins that are produced by keratinocytes. We therefore focused on the role of LN-5 when M . leprae is internalized by HEKn cells. Our results show that M . leprae preferentially binds to LN-5-coated slides and this binding to LN-5 enhances its binding to HEKn cells. The findings also show that pre-treatment with an antibody against α-DG, integrin-β1, or -β4 inhibited the binding of LN-5-coated M . leprae to HEKn cells. These results suggest that M . leprae binds to keratinocytes by taking advantage of the interaction of LN-5 in the basal lamina of the epidermis and a surface receptor of keratinocytes, such as α-DG, integrin-β1, or -β4.

In search of biomarkers for leprosy by unraveling the host immune response to Mycobacterium leprae

“…63 M leprae attachment to keratinocytes is probably mediated via laminin-5, the predominant form of laminin in the dermis. 64 Subsequent phagocytosis of M leprae by keratinocytes induced the production of antimicrobial cathelicidin, TNFα, and IL-1β in vitro, suggesting a key role for keratinocytes in initiating the primary immune response in the skin. 65 Keratinocytes can also function as an antigen-presenting cell (APC) and have been shown to present M leprae antigens to CD4 T-cells via MHC class II.…”

“…Differential expression of genes associated with keratinocyte biology have been identified, especially in BT patients, confirming a role of these cells in leprosy pathology 63 . M leprae attachment to keratinocytes is probably mediated via laminin‐5, the predominant form of laminin in the dermis 64 . Subsequent phagocytosis of M leprae by keratinocytes induced the production of antimicrobial cathelicidin, TNF‐α, and IL‐1β in vitro, suggesting a key role for keratinocytes in initiating the primary immune response in the skin 65 .…”

Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis

“…Many different studies have illustrated that α-DG plays a role in epithelialization, myogenesis and neurogenesis during embryonic development and postnatally, including the assembly of basement membranes, cell shape and polarity formation, tissue integrity maintenance, and cell survival and differentiation in many tissues [8,14,17,23,25,28,30,[46][47][48]. Also, DG serves as a receptor for several members of the arenavirus family, by virtue of high-affinity binding to α-DG of their envelope glycoproteins, and for the prokaryote Mycobacterium leprae indirectly through its ability to bind laminin, allowing the entrance of these pathogens into human cells [17,39,49,50]. Furthermore, as a DGC component β-DG serves as a scaffold for the organization of adhesion structures, integrin-mediated signal transduction systems, including the phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) (also known as Raf/Ras/MEK/ERK) pathways [27,[51][52][53], and modulation of nuclear structure and function (Fig.…”

Laminins Regulate Placentation and Pre-eclampsia: Focus on Trophoblasts and Endothelial Cells

“…For instance, LNα5 gene mutation leads to defects in neural tube closure, finger separation, placentation, kidney formation, pulmonary lobe separation, hair morphogenesis, and intestinal smooth muscle differentiation (Miner and Li, 2000;Nguyen et al, 2002;Bolcato-Bellemin et al, 2003). Integrins, dystroglycan, syndecans, and Lutheran/basal cell adhesion molecule (BCAM) are cellular receptors for LNs (Desgrosellier and Cheresh, 2010;Aumailley, 2018;Jin et al, 2019). The biological effects of LNs are presumably largely mediated by surface receptors that link LN matrices to intracellular signaling pathways [as reviewed in Durbeej (2010)].…”