Herpes simplex virus type 1 inflammasome activation in proinflammatory human macrophages is dependent on NLRP3, ASC, and caspase-1

Abstract

The proinflammatory cytokines interleukin (IL)-1β and IL-18 are products of activation of the inflammasome, an innate sensing system, and important in the pathogenesis of herpes simplex virus type 1 (HSV-1). The release of IL-18 and IL-1β from monocytes/macrophages is critical for protection from HSV-1 based on animal models of encephalitis and genital infection, yet if and how HSV-1 activates inflammasomes in human macrophages is unknown. To investigate this, we utilized both primary human monocyte derived macrophages and human monocytic cell lines (THP-1 cells) with various inflammasome components knocked-out. We found that HSV-1 activates inflammasome signaling in proinflammatory primary human macrophages, but not in resting macrophages. Additionally, HSV-1 inflammasome activation in THP-1 cells is dependent on nucleotide-binding domain and leucine-rich repeat-containing receptor 3 (NLRP3), apoptosis-associated speck-like molecule containing a caspase recruitment domain (ASC), and caspase-1, but not on absent in melanoma 2 (AIM2), or gamma interferon-inducible protein 16 (IFI16). In contrast, HSV-1 activates non-canonical inflammasome signaling in proinflammatory macrophages that results in IL-1β, but not IL-18, release that is independent of NLRP3, ASC, and caspase-1. Ultraviolet irradiation of HSV-1 enhanced inflammasome activation, demonstrating that viral replication suppresses inflammasome activation. These results confirm that HSV-1 is capable of activating the inflammasome in human macrophages through an NLRP3 dependent process and that the virus has evolved an NLRP3 specific mechanism to inhibit inflammasome activation in macrophages.

The Crucial Role of NLRP3 Inflammasome in Viral Infection-Associated Fibrosing Interstitial Lung Diseases

“…Furthermore, HSV-1 induced transcription of molecular pathways that promote fibrotic in IPF [ 99 ]. Supporting the previous study, Karaba et al found HSV-1 activates canonical and non-canonical NLRP3 inflammasome pathways to lead to the release of IL-1β [ 100 ]. In a bleomycin-induced mouse model, scutellarin suppressed excessive EMT and inflammation via NF-κβ/NLRP3 pathway [ 101 ].…”

Immune Response to Herpes Simplex Virus Infection and Vaccine Development

“…IFI16 interacts directly with interferon-β, inducing DNA to recruit IRF3 and NF-κB for the transcription of genes involved in inflammatory response. In a recent publication, HSV-1 was shown to also activate the inflammatory response via the nucleotide-binding domain and leucine-rich repeat-containing receptor 3 (NLRP3) [ 44 ].…”

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

“…Human monocytes can be obtained from freshly isolated PBMCs according to established protocols [ 12 , 80 ] and differentiated into human monocyte-derived macrophages (hMDMs). To this purpose, different approaches have been developed where different stimuli can be used in order to obtain a specific macrophage polarization [ 12 , 81 , 82 ]. For example, M-CSF-differentiated hMDMs treated with LPS/IFNγ or IL-4, become polarized toward the M1 or M2 phenotype, respectively [ 83 , 84 ].…”