Keratinocytes regulate intraepithelial lymphocytes homing and mediate mucosal barrier integrity via JAK2/STAT3 signaling in oral lichen planus.

INTRODUCTION

Oral lichen planus (OLP) is a common T-cell-mediated inflammatory disease affecting the oral mucosa. Intraepithelial lymphocytes (IELs), a unique subset of T cells, play a crucial role in regulating mucosal immune responses. However, the mechanisms by which keratinocytes (KCs) regulate the homing migration of OLP IELs and their involvement in mucosal barrier disruption remain unclear.

METHODS

This study conducted colocalization and quantitative analysis of the expression of E-cadherin, CD103, CD8α, ZO-1, and Occludin. A three-dimensional simulation homing model of oral mucosal tissue was constructed. Short hairpin RNAs (shRNAs) were designed to inhibit E-cadherin and CD103 of KCs and OLP IELs. The JAK/STAT pathway was inhibited using AG490 and ruxolitinib (RPM). The expression levels of ZO-1 and occludin were detected.

RESULTS

CD8α and CD103 were highly expressed in OLP, while the expression of E-cadherin, ZO-1, and Occludin was decreased. Silencing KCs' E-cadherin and IELs' CD103 significantly inhibited the homing migration of OLP IELs. After inhibiting the JAK/STAT pathway, KCs proliferation was reduced, while Bax and caspase-3 expression were upregulated and Bcl-2 expression was downregulated. The homing migration of OLP IELs was inhibited, with decreased expression of p-JAK2/JAK2 and p-STAT3/STAT3. Furthermore, ZO-1 and Occludin were upregulated.

DISCUSSION: The regulation of KCs on homing migration of OLP IELs depended on KCs' E-cadherin and IELs' CD103. By downregulating JAK2/STAT3 phosphorylation, KCs proliferation was inhibited and apoptosis was induced, which has therapeutic benefits for OLP epithelial dysplasia. Meanwhile, upregulation of mucosal barrier molecule expression helps maintain the integrity of the mucosal barrier.