Interleukin-1 receptor mediates the interplay between CD4+ T cells and ocular resident cells to promote keratinizing squamous metaplasia in Sjögren's syndrome.
Keratinizing squamous metaplasia (SQM) of the ocular mucosal epithelium is a blinding corneal disease characterized by the loss of conjunctival goblet cells (GCs), pathological ocular surface keratinization and tissue recruitment of immune cells. Using the autoimmune regulator (Aire)-deficient mouse as a model for Sjögren's syndrome (SS)-associated SQM, we identified CD4(+) T lymphocytes as the main immune effectors driving SQM and uncovered a pathogenic role for interleukin-1 (IL-1). IL-1, a pleiotropic cytokine family enriched in ocular epithelia, governs tissue homeostasis and mucosal immunity. Here, we used adoptive transfer of autoreactive CD4(+) T cells to dissect the mechanism whereby IL-1 promotes SQM. CD4(+) T cells adoptively transferred from both Aire knockout (KO) and Aire/IL-1 receptor type 1 (IL-1R1) double KO donors conferred SQM to severe-combined immunodeficiency (scid) recipients with functional IL-1R1, but not scid recipients lacking IL-1R1. In the lacrimal gland, IL-1R1 was primarily immunolocalized to ductal epithelium surrounded by CD4(+) T cells. In the eye, IL-1R1 was expressed on local mucosal epithelial and stromal cells, but not on resident antigen-presenting cells or infiltrating immune cells. In both tissues, autoreactive CD4(+) T-cell infiltration was only observed in the presence of IL-1R1-postive resident cells. Moreover, persistent activation of IL-1R1 signaling led to chronic immune-mediated inflammation by retaining CD4(+) T cells in the local microenvironment. Following IL-1R1-dependent infiltration of CD4(+) T cells, we observed SQM hallmarks in local tissues-corneal keratinization, conjunctival GC mucin acidification and epithelial cell hyperplasia throughout the ocular surface mucosa. Proinflammatory IL-1 expression in ocular epithelial cells significantly correlated with reduced tear secretion, while CD4(+) T-cell infiltration of the lacrimal gland predicted the development of ocular SQM. Collectively, data in this study indicated a central role for IL-1 in orchestrating a functional interplay between immune cells and resident cells of SS-targeted tissues in the pathogenesis of SQM.
Francis I Proctor Foundation, University of California at San Francisco, San Francisco, CA 94143, USA.
Ying-Ting
YT
Chen
Stanislav
S
Lazarev
Ahmad F
AF
Bahrami
Lisa B
LB
Noble
Feeling Y T
FY
Chen
Delu
D
Zhou
Marianne
M
Gallup
Mahesh
M
Yadav
Nancy A
NA
McNamara
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D020397:Goblet Cells / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism; D007638:Keratoconjunctivitis Sicca / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007765:Lacrimal Apparatus / Q000276:immunology / Q000378:metabolism; D008679:Metaplasia / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D007375:Interleukin-1; D017472:Receptors, Interleukin-1