Histamine Deficiency Inhibits Lymphocyte Infiltration in the Lacrimal Gland of Aged Mice

Aging is associated with chronic low-grade inflammation of exocrine glands, such as the lacrimal glands. Histamine, synthesized by histidine decarboxylase (HDC), is implicated in immune modulation; however, its role in age-related lacrimal gland inflammation remains unclear. To explore the role of histamine in age-related lacrimal gland inflammation, we compared wild-type and histidine decarboxylase knockout (HDC-KO) C57BL/6 mice at 6 weeks and 12 months of age (10 males and 10 females in each group). Histological and immunohistochemical analyses were performed to assess lymphocytic infiltration, mast cells, and the expression of cytokines and adhesion molecules. Gene expression levels were quantified using reverse transcriptase quantitative PCR (RT-qPCR). Aged wild-type mice showed significant upregulation of mRNA transcription of HDC and histamine H1 receptor, along with increased infiltration of B220-positive B cells and CD3-positive T cells in the lacrimal gland. The mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and ICAM-1 were elevated with age, whereas these changes were attenuated in HDC-KO mice. The mRNA expression of PPARγ, an anti-inflammatory factor, was upregulated in the aged HDC-KO mice. Mast cell numbers increased with age but did not differ according to sex. These findings suggest that histamine, via HDC and H1 receptor signaling, contributes to age-associated lacrimal gland inflammation by enhancing cytokine and ICAM-1 expression. HDC deficiency suppresses this inflammatory response, potentially through the upregulation of PPARγ. Thus, histamine may be a key mediator of age-related inflammation in the lacrimal gland and a potential therapeutic target.