Male Lacrimal Gland Research Articles

Type I Interferon Signaling Is Required for Dacryoadenitis in the Nonobese Diabetic Mouse Model of Sjögren Syndrome.

Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known. Here, we studied the effects of Treg depletion in hormone-manipulated NOD mice and lacrimal gland gene expression to determine early signals required for lacrimal gland inflammation. While Treg-depletion was not sufficient to drive dacryoadenitis in castrated male NOD mice, chemokines (Cxcl9, Ccl19) and other potentially disease-relevant genes (Epsti1, Ubd) were upregulated in male lacrimal glands. Expression of Cxcl9 and Ccl19, in particular, remained significantly upregulated in the lacrimal glands of lymphocyte-deficient NOD-severe combined immunodeficiency (SCID) mice and their expression was modulated by type I interferon signaling. Notably, Ifnar1-deficient NOD mice did not develop dacryoadenitis. Together these data identify disease-relevant genes upregulated in the context of male-specific dacryoadenitis and demonstrate a requisite role for type I interferon signaling in lacrimal gland autoimmunity in NOD mice.

Sex differences in expression and differential regulation by androgen and estrogen of two odorant-binding tear lipocalins in lacrimal glands of immature hamsters

In adults of several mammalian species, lacrimal glands (LG) have sex differences but there is no report of any sexual dimorphism in LG of immatures. In LG and tears of adult hamsters, we found female-specific expression of two closely related odorant-/pheromone-binding lipocalins, FLP ( female lacrimal protein) and MSP ( male- specific protein; initially identified in salivary glands of males). Although, both androgens and estrogens markedly repress FLP and MSP in LG of adults, the expression of these lipocalins in females is due to their incomplete repression by endogenous estrogens. Here we report a marked sexual dimorphism in the expression of FLP and MSP in LG and tears of 20-day-old immature hamsters. The age-dependant expression of these lipocalins and effect of neonatal-gonadectomy and sex hormone treatments on their expression in immatures was investigated. FLP and MSP are detectable in LG at 10-day age in both sexes of hamster but by 20-day age levels of both lipocalins show sex differences wherein FLP is several fold higher in males and MSP is obliterated in males. Thereafter, FLP declines in male LG and is obliterated by 36-day age, resulting in female-specific expression of both LG lipocalins as seen in adults. In LG of 20-day-old immatures, FLP and MSP are insensitive to repression by androgen and estrogen, respectively, which was unlike the androgen/estrogen-repressed regulation of both lipocalins in adult LG. The estrogenic repression of FLP and androgenic repression of MSP in LG of immature hamsters could be prevented by treatment with tamoxifen and flutamide, respectively. Our studies indicate that (i) presence of gonads in immatures can have significant effects on LG lipocalins resulting in their sexually dimorphic expression, (ii) in immatures, unlike adults, the repressive effects of estrogen and androgen on LG lipocalins are selective for FLP and MSP, respectively, and (iii) these repressions are likely to be mediated by sex hormone receptors.

A novel mouse protein differentially regulated by androgens in the submandibular and lacrimal glands

We characterized a cDNA clone derived from the female mouse submandibular gland (SMG). The transcript of this cDNA was approximately 1.2 kb in size and predicted to code a 165-amino acid protein with a putative signal peptide for a secretory pathway. This protein, named submandibular androgen-repressed protein (SMARP), had homology in the N-terminal region with members of the glutamine/glutamic acid-rich protein (GRP) family from rats. Northern blot analysis revealed that SMARP mRNA is expressed, out of the major mouse organs, only in the SMG and exorbital lacrimal gland (LG), with much more abundance in the former. For the SMG, the level of SMARP mRNA was 36 times higher in females than males, whereas for the LG it was 28 times higher in males than females. Furthermore, the level of SMARP mRNA was increased in the SMG but reduced in the LG with castration in males, whereas it was reduced in SMG but increased in LG after administration of testosterone in females or castrated males. In situ hybridization detected the signal for SMARP mRNA in the female SMG, and immunohistochemistry detected the signal for SMARP protein in the female SMG and male LG. In the female SMG, SMARP mRNA, and protein were localized intensively in a subpopulation of acinar cells, whereas in the male LG, SMARP protein was distributed diffusely in all acinar cells. These results suggested that SMARP is a secretory protein whose expression is regulated by androgens negatively in the SMG and positively in the LG.

Role of gap junctions in fluid secretion of lacrimal glands.

In glands such as the liver and pancreas, gap junctions containing connexin 26 and 32 (Cx26 and Cx32, respectively) couple the secretory cells. Uncoupling these junctions compromises the secretory function of these glands. Lacrimal glands also contain extensive arrays of gap junctions consisting of Cx26 and Cx32. We wanted to determine the role of these junctions in fluid secretion. In Cx32-deficient mice, immunocytochemistry showed that, in the male lacrimal gland, the remaining Cx26 was found evenly distributed in the membrane whereas there was little in the membranes of female glands. Western blot analysis of Cx26 showed that female Cx32-deficient mice expressed Cx26. Patch-clamp analyses of acinar cell coupling showed that the cell pairs from male glands were coupled whereas those from female glands were not. Stimulated fluid production by the glands from Cx32-deficient mice was abnormally low in female glands compared with controls at low topical doses of carbachol. The protein secretory response to different doses of carbachol was the same in all animals. These data suggest that gap junctions are essential for optimal fluid secretion in lacrimal glands.