IFN-γ Primes Keratinocytes for HSV-1–Induced Inflammasome Activation

Abstract

Inflammasomes are immune complexes that induce an inflammatory response upon sensing of different stress signals. This effect is mainly mediated by activation and secretion of the proinflammatory cytokines proIL-1β and -18. Here we report that infection of human primary keratinocytes with the double-stranded DNA viruses modified vaccinia virus Ankara (MVA) or herpes simplex virus type 1 (HSV-1)-induced secretion of mature IL-1β and -18. This secretion was dependent on several inflammasome complexes; however, the absent in melanoma 2 (AIM2) inflammasome, which is activated by binding of double-stranded DNA, played the most important role. Whereas prestimulation of keratinocytes with IFN-γ moderately increased MVA-induced IL-1β and IL-18 secretion, it was essential for substantial secretion of these cytokines in response to herpes simplex virus type 1 infection. IFN-γ partially restored HSV-1 suppressed proIL-1β expression and was also required for inflammasome activation. Most importantly, IFN-γ strongly suppressed virus replication in keratinocytes in vitro and ex vivo, which was independent of inflammasome activation. Our results suggest that, similar to Herpesviridae infection in mice, HSV-1 replication in human skin is controlled by a positive feedback loop of keratinocyte-derived IL-1/IL-18 and IFN-γ expressed by immune cells.

Interferon-induced guanylate-binding proteins in inflammasome activation and host defense

“…These signals include pathogen- and endogenous danger-associated molecular patterns (PAMPs and DAMPs) detected largely in the cytosol of macrophages, monocytes, splenic and plasmacytoid dendritic cells, T and B cells, neutrophils, keratinocytes and inflamed endothelium 5,9,10,16,25-28 . Complex assembly leads to caspase-1-dependent cleavage of pro-interleukin 1β (pro-IL-1β) and pro-IL-18 to their mature exported forms as part of the canonical inflammasome pathway.…”

“…IFN-induced transcription factors STAT1 and IRF1 likewise elicit AIM2-dependent cytokine and cell death responses to Francisella novicida 22,23 . In addition, type II IFN-γ enhances AIM2-induced IL-1β release or NLRP3-dependent pro-IL-18 cleavage during HSV-1 and Chlamydia muridarum infections 16,20 . Here IFN-γ-induced upregulation of NLRP3, ASC and procaspase-1 expression may help lower the PAMP-triggered activation threshold by ~5–20 fold due to increased core protein levels 12,17,18,20 .…”

AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

“…Absent in melanoma 2 (AIM2), a member of the pyrin and HIN200 domain-containing protein family (3)(4)(5), is an intracellular pattern recognition receptor that can form an inflammasome by directly binding to dsDNA from virus, bacteria, or the host itself (5-7). The role of the AIM2 inflammasome has been reported in many viral infections including murine CMV, vaccinia, and HSV (7)(8)(9)(10)(11), and is critical in defense against the cytosolic bacterium Francisella and Listeria monocytogenes and Mycobacterium tuberculosis (12)(13)(14). To date, very little is known about whether the AIM2 inflammasome is activated during RNA virus infections, including influenza A virus (IAV), which can cause life-threatening diseases, especially in high-risk groups.…”

Epicutaneous administration of the pattern recognition receptor agonist polyinosinic‐polycytidylic acid activates the MDA5/MAVS pathway in Langerhans cells

“…p(I:C) is primarily sensed by 4 intracellular receptors: cytoplasmic IFN-inducible RNA-dependent protein kinase R (PKR) (29), as well as viral sensing pattern recognition receptors (PRRs). These include endosomal TLR3 and cytoplasmic retinoic acid–inducible gene I (RIG-I)-like receptors (RLRs) [RIG-I, melanoma differentiation–associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2)] (30, 31). RIG-I, MDA5, and LGP2 are expressed ubiquitously, but only RIG-I and MDA5 possess N-terminal caspase activation and recruitment domains that are capable of downstream immune signal transduction (32).…”