TLR7 and TLR8 Differentially Activate the IRF and NF-κB Pathways in Specific Cell Types to Promote Inflammation

Abstract

TLR7 and TLR8 are pattern recognition receptors that reside in the endosome and are activated by ssRNA molecules. TLR7 and TLR8 are normally part of the antiviral defense response, but they have also been implicated as drivers of autoimmune diseases such as lupus. The receptors have slightly different ligand-binding specificities and cellular expression patterns that suggest they have nonredundant specialized roles. How the roles of TLR7 and TLR8 differ may be determined by which cell types express each TLR and how the cells respond to activation of each receptor. To provide a better understanding of the effects of TLR7/8 activation, we have characterized changes induced by TLR-specific agonists in different human immune cell types and defined which responses are a direct consequence of TLR7 or TLR8 activation and which are secondary responses driven by type I IFN or cytokines produced subsequent to the primary response. Using cell sorting, gene expression analysis, and intracellular cytokine staining, we have found that the IFN regulatory factor (IRF) and NF-kB pathways are differentially activated downstream of the TLRs in various cell types. Studies with an anti-IFNAR Ab in human cells and lupus mice showed that inhibiting IFN activity can block secondary IFN-induced gene expression changes downstream of TLR7/8 activation, but not NF-kB-regulated genes induced directly by TLR7/8 activation at earlier timepoints. In summary, these results elucidate the different roles TLR7 and TLR8 play in immunity and inform strategies for potential treatment of autoimmune diseases driven by TLR7/8 activation. ImmunoHorizons, 2020, 4: 93-107.

Overcoming Barriers for siRNA Therapeutics: From Bench to Bedside

“…It has been observed that plasmacytoid dendritic cells (pDCs), B cells, and monocytes express TLR7. At the same time, TLR8 is expressed by myeloid DC (mDC) and macrophages in humans [ 89 ]. TLR7 has been shown to detect single-stranded RNA (ssRNA), polyuridine, as well as synthetic ssRNA rich in uridine along with guanosine [ 90 ].…”

SARS-CoV-2 Treatment Approaches: Numerous Options, No Certainty for a Versatile Virus

“…Cq is currently studied in multiple clinical trials, either in monotherapy (ChiCTR2000029609) or in combination with other drugs such as remdesivir . Similarly, Hq sulfate (a less toxic derivate of Cq) also displays an activity spectrum which includes coronaviruses, in addition to its immunomodulatory potential through the inhibition of TLR7, 8 signalling and the suppression of TNF-a and IL6 synthesis (Picot et al, 1993;Jang et al, 2006;Bender et al, 2020). These therapeutic molecules showed an additional effect during both the entry and post-entry stages of SARS-CoV-2, as was also shown in Vero E6 cells, and were included in March 2020 in the Chinese guidelines for the management of COVID-19 (Vincent et al, 2005;Yao et al, 2020).…”

“…Remdesivir is an adenosine analogue which also controls mTORC1 signalling and has a wide spectrum against coronaviruses including resistant strains (Sheahan et al, 2017;Agostini et al, 2018). Remdesivir has shown in vitro activity against SARS-CoV-2 in combination with chloroquine or in monotherapy, as part of a 10-day intravenous treatment in COVID-19 patients with severe pneumonia (Adaptive COVID-19 Treatment Trial ACTT-NCT04280705) (Beigel et al, 2020). Moreover, the intravenous use of remdesivir on a compassionate-use basis to patients with SARS-CoV-2 infection receiving oxygen support, has been associated with a clinical improvement in 68% of patients, according to a study published in April by Grein et al (2020).…”

“…Meplazumab (mAb antiCD147 receptor) (Wang K. et al, 2020) NCT04275245 Clathrin-mediated endocytosis Hydroxychloroquine (Hq) sulphate (Picot et al, 1993;Jang et al, 2006;Bender et al, 2020) and Chloroquine phosphate (Savarino et al, 2003;Vincent et al, 2005) *multiple targets: clathrin-mediated endocytosis, endosomal Ph, TLR7/8, IFN response, and proinflammatory cytokines release) Controversial results: (Borba et al, 2020;Lane et al, 2020;Shamshirian et al, 2020;Tu et al, 2020) -ongoing studies NCT04315948, DisCoVeRy trial, NCT04304053 ChiCTR2000029803, NCT04334148, ChiCTR2000029609 --discontinued study: Hq arm of Solidarity trial -withdrawn: NCT04347512, NCT04371926…”

“…Protease inhibitors: lopinavir/darunavir/ritonavir (3CLpro, PLpro) RECOVERY trial, NCT04251871, NCT04255017, ChiCTR2000029539 NCT04252274, NCT04295551, ChiCTR2000029308, NCT04252274 Remdesivir * (Sheahan et al, 2017;Agostini et al, 2018;Beigel et al, 2020;Goldman et al, 2020;Grein et al, 2020;Wu et al, 2020a; *multiple targets: viral autophagy, mTORC1, Nsp12-RdRp, replicase/ transcription complex -RTC Trial ACTT-NCT04280705 si ACTT-II, NCT04292899 NCT04257656, SIMPLE trial, WHO Solidarity trial, DisCoVeRy trial Favipiravir/target: Nsp12-RdRp) (Coomes and Haghbayan, 2020) ChiCTR2000030254, ChiCTR2000029544 ChiCTR2000029600 Cytokine response, Th1 response IFN administration (Hung et al, 2020) Controversial results (Gandhi, 2020) See Table 1 Ruxolitinib (anti-Janus kinase inhibitor) (Gaspari et al, 2020;Yeleswaram et al, 2020) NCT04362137…”