TILRR Promotes Migration of Immune Cells Through Induction of Soluble Inflammatory Mediators

Abstract

TILRR has been identified as an important modulator of inflammatory responses. It is associated with NF-κB activation, and inflammation. Our previous study showed that TILRR significantly increased the expression of many innate immune responsive genes and increased the production of several pro-inflammatory cytokines/chemokines by cervical epithelial cells. In this study, we evaluated the effect of TILRR-induced proinflammatory cytokines/chemokines on the migration of immune cells. The effect of culture supernatants of TILRR-overexpressed cervical epithelial cells on the migration of THP-1 monocytes and MOLT-4 T-lymphocytes was evaluated using Transwell assay and a novel microfluidic device. We showed that the culture supernatants of TILRR-overexpressed HeLa cells attracted significantly more THP-1 cells (11-40%, p = 0.0004-0.0373) and MOLT-4 cells (14-17%, p = 0.0010-0.0225) than that of controls. The microfluidic device-recorded image analysis showed that significantly higher amount with longer mean cell migration distance of THP-1 (p < 0.0001-0.0180) and MOLT-4 (p < 0.0001-0.0025) cells was observed toward the supernatants of TILRR-overexpressed cervical epithelial cells compared to that of the controls. Thus, the cytokines/chemokines secreted by the TILRR-overexpressed cervical epithelial cells attracted immune cells, such as monocytes and T cells, and may potentially influence immune cell infiltration in tissues.

The Potential Role of FREM1 and Its Isoform TILRR in HIV-1 Acquisition through Mediating Inflammation

“…We examined the migration behavior of cells in Transwell assay and microfluidic device assay. Our data showed that monocytes (THP-1) and T-lymphocytes (MOLT-4) migrated significantly towards the TILRR-overexpressed cell culture supernatants and migrated longer distances [69]. Therefore, the data showed that TILRR-modulated production of soluble mediators can promote migration of immune cells, and have a potential role in inflammation-induced vaginal HIV-1 acquisition by attracting immune cells to the site of inflammation.…”

“…NF-κB transcription factor is one of the central regulators of many inflammatory genes [66] and inflammation [67,71]. NF-κB activation is potentiated by the association of TILRR with IL-1R1 receptor [4,65], and TILRR-associated NF-κB activation instigates the production of inflammatory cytokines/chemokines, and migration of immune cells [16,58,69]. Since cervical epithelial tissues express a high level of FREM1 mRNA [15], and TILRR is an isoform of FREM1 [60] and a major modulator of many inflammatory responsive genes in the NF-κB pathway [16], the expression of FREM1/TILRR in genital epithelial tissues may augment the inflammatory responses via NF-κB activation and the production of inflammatory mediators.…”

“…Since cervical epithelial tissues express a high level of FREM1 mRNA [15], and TILRR is an isoform of FREM1 [60] and a major modulator of many inflammatory responsive genes in the NF-κB pathway [16], the expression of FREM1/TILRR in genital epithelial tissues may augment the inflammatory responses via NF-κB activation and the production of inflammatory mediators. We, therefore, propose a model depicting the potential roles of FREM1/TILRR in vaginal HIV-1 acquisition through mediating inflammation (Figure 4A-D) based on our in vitro studies [16,69], a genetic study [15] and a number of related publications [24,25,47,58,70]. , the high-level expression of FREM1/TILRR increases the production of pro-inflammatory cytokines/chemokines by epithelial cells [16].…”

“…, the high-level expression of FREM1/TILRR increases the production of pro-inflammatory cytokines/chemokines by epithelial cells [16]. The increased production of pro-inflammatory cytokines/chemokines attracts the infiltration of immune cells from the periphery to the cervical tissues, including HIV-1 target cells [24,69,72]. The cytokines secreted by the infiltrated immune cells may further activate and attract more immune cells and resulted in cycles of inflammation and breakdown of epithelial barrier.…”

High level of plasma TILRR protein is associated with faster HIV seroconversion

“… 1 Our studies showed that TILRR is a major modulator of many inflammatory responsive genes in the NF-κB signal transduction pathway, increases chemokine and cytokine secretion by epithelial cells, and promotes migration of immune cells. 2 , 3 Inflammation promotes activation and localization of HIV target cells, and elevated cervicovaginal inflammation has been associated with a higher risk of HIV acquisition. 4 , 5 , 6 , 7 , 8 , 9 …”