Differential recognition of HIV-stimulated IL-1β and IL-18 secretion through NLR and NAIP signalling in monocyte-derived macrophages

Triantafilou, K; Ward, CJK; Czubala, M; Ferris, RG; Koppe, E; Haffner, C; Piguet, V; Patel, VK; Amrine-Madsen, H; Modis, L; Masters, SL; Triantafilou, M

Author(s): Triantafilou, K; Ward, CJK; Czubala, M; Ferris, RG; Koppe, E; Haffner, C; Piguet, V; Patel, VK; Amrine-Madsen, H; Modis, L; Masters, SL; Triantafilou, M;
Details: Publication Year 2021-04-16,Volume 17,Issue #4,Page e1009417
Journal Title: PLoS Pathogens
Abstract: Macrophages are important drivers of pathogenesis and progression to AIDS in HIV infection. The virus in the later phases of the infection is often predominantly macrophage-tropic and this tropism contributes to a chronic inflammatory and immune activation state that is observed in HIV patients. Pattern recognition receptors of the innate immune system are the key molecules that recognise HIV and mount the inflammatory responses in macrophages. The innate immune response against HIV-1 is potent and elicits caspase-1-dependent pro-inflammatory cytokine production of IL-1β and IL-18. Although, NLRP3 has been reported as an inflammasome sensor dictating this response little is known about the pattern recognition receptors that trigger the "priming" signal for inflammasome activation, the NLRs involved or the HIV components that trigger the response. Using a combination of siRNA knockdowns in monocyte derived macrophages (MDMs) of different TLRs and NLRs as well as chemical inhibition, it was demonstrated that HIV Vpu could trigger inflammasome activation via TLR4/NLRP3 leading to IL-1β/IL-18 secretion. The priming signal is triggered via TLR4, whereas the activation signal is triggered by direct effects on Kv1.3 channels, causing K+ efflux. In contrast, HIV gp41 could trigger IL-18 production via NAIP/NLRC4, independently of priming, as a one-step inflammasome activation. NAIP binds directly to the cytoplasmic tail of HIV envelope protein gp41 and represents the first non-bacterial ligand for the NAIP/NLRC4 inflammasome. These divergent pathways represent novel targets to resolve specific inflammatory pathologies associated with HIV-1 infection in macrophages.
Publisher: PLOS
Research Division(s): Inflammation
PubMed ID: 33861800
Publisher's Version: https://doi.org/10.1371/journal.ppat.1009417
Open Access at Publisher's Site: https://doi.org/10.1371/journal.ppat.1009417
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Triantafilou K et al_PLoS Pathogens_2021.pdf - (3.21MB, application/pdf)

Creation Date: 2021-05-11 02:09:56

Last Modified: 2021-05-11 04:06:35