Accumulation of Catalytically Active Proteases in Lacrimal Gland Acinar Cell Endosomes During Chronic <i>Ex Vivo</i> Muscarinic Receptor Stimulation

Rose, C.M.; Li, Qian; Hakim, Lawrence S.; Wang, Y.; Jerdeva, G. Y.; Marchelletta, Ronald R.; Nakamura, T.; Hamm‐Alvarez, Sarah F.; Mircheff, Austin K.

doi:10.1111/j.0300-9475.2005.01527.x

Cited by 22 publications

(20 citation statements)

References 44 publications

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“…Proteins that are destined to function in the lysosome follow the common biosynthetic pathway from the endoplasmic reticulum to the TGN, when the lysosomal proteins are targeted to the late endosome, both directly and by way of the early and recycling endosomes. Other work (32) establishes that this traffic is sensitive to the signaling milieu. Chronic stimulation with 10 M CCh blocks movement to the late endosome from both the TGN and the early endosome, with the consequence that catalytically active lysosomal proteases accumulate in the TGN, early endosome, recycling endosome, and immature secretory vesicle.…”

Section: Discussionmentioning

confidence: 98%

“…8. Key features of the endosomal traffic pathways were established through studies of the traffic of 125 I-labeled epidermal growth factor, which acinar cells internalize by receptor-mediated endocytosis and traffic in a biphasic manner, first to the recycling endosome and then to the prelysosome and lysosome (48), and of 125 I-BSA, which acinar cells internalize by fluid phase endocytosis and traffic primarily to the late endosome, prelysosome, and lysosome (32). The classic regulated secretory pathway has been examined most recently in studies of the stimulation-induced dynamics of actin-GFP (17) and traffic of syncollin-GFP (18).…”

Section: Discussionmentioning

confidence: 99%

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Elevated prolactin redirects secretory vesicle traffic in rabbit lacrimal acinar cells

Wang¹,

Chiu²,

Nakamura³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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-During pregnancy, lymphocytes infiltrating the rabbit lacrimal gland disperse to the interacinar space from their normal focal concentrations, basal fluid secretion decreases, pilocarpine-induced fluid secretion increases, and stimulated fluid protein concentration decreases. Ductal epithelial cell prolactin (PRL) content increases and redistributes from the apical to the basal-lateral cytoplasm. A replication-incompetent adenovirus vector for rabbit PRL (AdPRL) was used to test the hypothesis that increased intracrine/autocrine PRL signaling alters secretory protein traffic in an ex vivo lacrimal acinar cell model. AdPRL had no discernable influence on microtubules or actin microfilaments or their responses to carbachol (CCh). Endogenous and transduced PRLs exhibited similar, nonpolarized, punctate distributions. Cells secreted PRL consititutively and at increased rates in response to CCh. In contrast, constitutive secretion of ␤-hexosaminidase was negligible, suggesting that the constitutive pathway for PRL is relatively inaccessible to typical secretory proteins. AdPRL had no significant effect on total secretion of ␤-hexosaminidase or syncollingreen fluorescent protein (GFP), a chimeric secretory protein construct. However, it reversed the polarized distributions of vesicles containing rab3D and syncollin-GFP. Live-cell imaging indicated that AdPRL redirected CCh-dependent syncollin-GFP exocytosis from the apical plasma membrane to the basal-lateral membrane. Elevated concentrations of exogenous rabbit PRL in the ambient medium elicited similar changes. These observations suggest that elevated PRL, as occurs in the physiological hyperprolactinemia of pregnancy, induces lacrimal epithelial cells to express a mixed exocrine/endocrine phenotype that secretes fluid to the acinus-duct lumen but secretes proteins to the underlying tissue space. This phenotype may contribute to the pregnancy-associated immunoarchitecture. ocular surface; mucosal immunity; pregnancy; Sjögren's syndrome THE OCULAR SURFACE SYSTEM maintains a thin fluid film that comprises an external milieu necessary for optimal homeostasis of its mucosal tissues and of the cornea. Disruptions of ocular surface homeostasis frequently elicit sensations of dryness, itching, or burning. These symptoms may be associated with immune system diseases, such as Sjögren's syndrome and graft vs. host disease, but most cases occur without the typical signs of autoimmune disease. They occur more frequently in women than men and are often associated with altered states of the systemic hormonal milieu: perimenopause, postmenopause, pregnancy, lactation, oral contraceptive use (39), and estrogen or estrogen-progesterone replacement therapy (35,36). Among men, the frequency increases with age (8).Aging in men is accompanied by gradual decreases in gonadal and adrenal production of androgens. The physiological states associated with altered ocular surface system homeostasis in women share one well-known common denominator, a decrease in the amount of testosterone that...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Elevated prolactin redirects secretory vesicle traffic in rabbit lacrimal acinar cells

Wang¹,

Chiu²,

Nakamura³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Prolonged exposure to 10 lM CCh does not disrupt the integrity of the epithelial monolayers, but it causes cytopathologic changes 23,24 ; it alters membrane vesicle-mediated intracellular traffic in a way that might alter the proteolytic processing of potential autoantigens 53 ; and it significantly decreases cytosolic Ca 2þ elevation, protein secretion, 23,24 and Cl À secretion (Fig. 3) in response to an optimal dose of CCh.…”

Section: Discussionmentioning

confidence: 99%

Diverse Mediators Modulate the Chloride Ion Fluxes That Drive Lacrimal Fluid Production

Selvam

Mircheff

Yiu³

2013

Invest. Ophthalmol. Vis. Sci.

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“…Regarding the autoantigen itself, little is known. Type 3 muscarinic acetylcholine receptor was proposed based on the presence of autoreactive serum from dry eye patients (51), and excessive acetylcholine receptor stimulation was demonstrated to expose cryptic type 3 muscarinic acetylcholine receptor epitopes to be sampled by APCs (52). Putative autoantigens were also identified from the kallikrein family, namely Klk13 and Klk1b22 (53,54).…”

Section: Cd11bmentioning

confidence: 99%

Ocular Surface APCs Are Necessary for Autoreactive T Cell-Mediated Experimental Autoimmune Lacrimal Keratoconjunctivitis

Schaumburg

Siemasko

Paiva

et al. 2011

The Journal of Immunology

136

126

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As specialized sentinels between the innate and adaptive immune response, APCs are essential for activation of Ag-specific lymphocytes, pathogen clearance, and generation of immunological memory. The process is tightly regulated; however, excessive or atypical stimuli may ignite activation of APCs in a way that allows self-Ag presentation to autoreactive T cells in the context of the necessary costimulatory signals, ultimately resulting in autoimmunity. Studies in both animal models and patients suggest that dry eye is a chronic CD4+ T cell-mediated ocular surface autoimmune-based inflammatory disease. Using a desiccating stress-induced mouse model of dry eye, we establish the fundamental role of APCs for both the generation and maintenance of ocular-specific autoreactive CD4+ T cells. Subconjunctival administration of liposome-encapsulated clodronate efficiently diminished resident ocular surface APCs, inhibited the generation of autoreactive CD4+ T cells, and blocked their ability to cause disease. APC-dependent CD4+ T cell activation required intact draining cervical lymph nodes, as cervical lymphadenectomy also inhibited CD4+ T cell-mediated dry eye disease. In addition, local depletion of peripheral conjunctival APCs blocked the ability of dry eye-specific CD4+ T cells to accumulate within the ocular surface tissues, suggesting that fully primed and targeted dry eye-specific CD4+ T cells require secondary activation by resident ocular surface APCs for maintenance and effector function. These data demonstrate that APCs are necessary for the initiation and development of experimental dry eye and support the standing hypothesis that dry eye is a self-Ag–driven autoimmune disease.

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Accumulation of Catalytically Active Proteases in Lacrimal Gland Acinar Cell Endosomes During Chronic Ex Vivo Muscarinic Receptor Stimulation

Cited by 22 publications

References 44 publications

Elevated prolactin redirects secretory vesicle traffic in rabbit lacrimal acinar cells

Elevated prolactin redirects secretory vesicle traffic in rabbit lacrimal acinar cells

Diverse Mediators Modulate the Chloride Ion Fluxes That Drive Lacrimal Fluid Production

Ocular Surface APCs Are Necessary for Autoreactive T Cell-Mediated Experimental Autoimmune Lacrimal Keratoconjunctivitis

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