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

Abstract

FREM1 (Fras-related extracellular matrix 1) and its splice variant TILRR (Toll-like interleukin-1 receptor regulator) have been identified as integral components of innate immune systems. The potential involvement of FREM1 in HIV-1 (human immunodeficiency virus 1) acquisition was suggested by a genome-wide SNP (single nucleotide polymorphism) analysis of HIV-1 resistant and susceptible sex workers enrolled in the Pumwani sex worker cohort (PSWC) in Nairobi, Kenya. The studies showed that the minor allele of a FREM1 SNP rs1552896 is highly enriched in the HIV-1 resistant female sex workers. Subsequent studies showed that FREM1 mRNA is highly expressed in tissues relevant to mucosal HIV-1 infection, including cervical epithelial tissues, and TILRR is a major modulator of many genes in the NF-κB signal transduction pathway. In this article, we review the role of FREM1 and TILRR in modulating inflammatory responses and inflammation, and how their influence on inflammatory responses of cervicovaginal tissue could enhance the risk of vaginal HIV-1 acquisition.

Keywords: FREM1; HIV-1 acquisition; TILRR; inflammation.

Figure 1

Diagram of FRAS/FREM family proteins, FREM1 splice variants (TILRR and others), and recombinant FREM1 proteins. (A) FRAS/FREM family proteins, including FREM1 (FREM1 isoform 1); (B) TILRR (FREM1 isoform 2) and other truncated variants of FREM1 identified in PBMCs (peripheral blood mononuclear cells) of women enrolled in the Pumwani sex worker cohort; (C) Recombinant FREM1 proteins (rFREM1 spD and rFREM1 spF). RGD, arginine-glycine-aspartic acid; CSPG, chondroitin sulfate proteoglycan; and GAG, glycosaminoglycan. This figure was adapted with permission from Kashem et al. [16], Short et al. [1], and Yuan et al. [29].

Figure 2

Full gene sequencing of FREM1 and RNA-Seq analysis of PBMCs. (A) Full gene sequencing of FREM1 gene of 70 women in the Pumwani sex worker cohort identified a novel microsatellite Tuff-ST that is in linkage disequilibrium with the SNP rs1552896 (LOD 20.15, D′ 0.931, r²: 0.04). Further Sanger sequencing and genotype of 1090 women for this microsatellite showed that rs1552896-Tuff-ST (SThomo) genotype is significantly associated with resistant women (p = 0.0002). (B) RNA-Seq analysis of PBMCs of Pumwani sex workers with different rs1552896-Tuff-ST genotypes. Women with the protective rs1552896-Tuff-ST (SThomo) genotype do not express or express a very low amount of FREM1 RNA isoform encoding TILRR in comparison with women with the rs1552896-Tuff-ST wild type (p = 0.0067) (Luo et al., unpublished data).

Figure 3

TILRR potentiates MYD88 recruitment to IL-1R1 to induce NF-κB signaling and inflammatory responses. TILRR binds with IL-1R1 as a co-receptor and potentiates the recruitment of MYD88 adapter to the cytoplasmic TIR domain. The association of adapter molecule with TIR domain induces the signal amplification and directs the Ras GTPase-controlled enhancement of NF-κB induction and inflammatory genes. This figure was adapted with permission from Zhang et al. [4].

Figure 4

Proposed model on the potential role of FREM1/TILRR in vaginal HIV-1 acquisition. (A) A schematic view of the female genital tract (FGT). (B) A close-up view of different layers of healthy cervical epithelial tissue. In figure B, the expression of FREM1/TILRR in healthy cervical tissue maintains the epithelial integrity, which prevents the invasion of pathogens including HIV-1 into the genital tissue. (C) A close-up view of different layers of HIV-1 susceptible cervical epithelial tissue. In figure C, 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. Studies showed that genital inflammation increases the risk of HIV-1 acquisition [24,25,70]. The proposed model showed that TILRR promotes the production of cytokines/chemokines by epithelial cells and attracts the infiltration of immune cells, including CD4+T-cells and macrophages [58], and it is a risk factor in HIV-1 acquisition. (D) A flow diagram shows the effect of FREM1/TILRR in vaginal HIV-1 acquisition through genital epithelium as illustrated in figure C. An upwards arrow represents increased and a downwards arrow indicates decreased. Legends on the upper right corner indicate the various immune components of the female genital tract. FGT, female genital tract; BM, basement membrane; MC, muscular; SS, serosae; MT, mesothelium; CTZ, cervical transformation zone; LFGT, lower female genital tract; UFGT, upper female genital tract; CTL, cytotoxic t-lymphocyte; T-REG, t-regulatory; FREM1, Fras-related extracellular matrix 1; and TILRR, toll-like interleukin-1 receptor regulator; ECM, extracellular matrix; HIV-1, human immunodeficiency virus type 1.