Toll-Like Receptor Signaling in the Pathogenesis of Chronic Dacryocystitis: Implication of c-FOS Transcription Factor and its Downstream Effector Chemokine Genes CCL2, CCL4, CXCL3, CXCR4 with a Shift of the M1/M2 Macrophage Phenotype

Abstract

Introduction: TLRs are fundamental elements in the orchestration of innate immune system. These receptors seem to be responsible for the inflammation and fibrosis in chronic dacryocystitis. The aim of the present study was to investigate the role of toll-Like receptors (TLR2 and TLR4) signaling pathway and its downstream effector chemokine genes in the pathogenesis of chronic dacryocystitis. Method: This study was conducted on 20 patients diagnosed with chronic dacryocystitis and underwent external dacryocystorhinostomy. Estimation of gene expression of TLR2, TLR4, CCL2, CCL4, CXCL3, CXCR4 and c-FOS genes in the lacrimal sac tissues was performed together with assessment of the inflammatory markers TNFα, IL-1β, IFN-γ and IL-22. Histopathological examination of the lacrimal sac walls using hematoxylin and eosin (H&E) stain, in addition to immunohistochemical staining of the CD68 and CD163 macrophage markers were also performed. Results: Our results showed that TLR2, TLR4 and c-FOS gene expressions were significantly increased in chronic dacryocystitis group with subsequent increase in their downstream effector chemokine genes CCL2, CCL4 and CXCL3. This up-regulation of genes was accompanied by macrophage shift of polarization toward the M1 pro-inflammatory phenotype (increased CD68 and decreased CD163 expression), leading to increased levels of the pro-inflammatory cytokines (TNF-α, IL-1β and IFN-γ) and decreased anti-inflammatory marker IL-22 with chronic dacryocystitis. Conclusion: It is essential to fine tune TLR activation through emerging therapeutic approaches. Targeting of TLR signaling at the level of receptors or downstream adaptor molecules represents a new challenge for treatment of chronic dacryocystitis.

LncRNA‐WAKMAR2 regulates expression of CLDN1 to affect skin barrier through recruiting c‐Fos

“…FOS/c-Fos, as a transcription factor, can bind to the promoter region of many genes to regulate their expression. 33 As mentioned above, DNA binding activity of AP-1 was almost completely lost or decreased in psoriatic lesions compared with normal skin. In this study, FOS knockdown can reduce the mRNA expression of tight junction genes (CLDN1/CLDN5/ZO-1/OCLN) and cornified envelopes (IVL).…”

“…Further, we found that FOS/c‐Fos expression was also significantly down‐regulated in skin lesions. FOS/c‐Fos, as a transcription factor, can bind to the promoter region of many genes to regulate their expression 33 . As mentioned above, DNA binding activity of AP‐1 was almost completely lost or decreased in psoriatic lesions compared with normal skin.…”