IL-36 promotes anti-viral immunity by boosting sensitivity to IFN-α/β in IRF1 dependent and independent manners

Abstract

The functions of the IL-36 cytokines remain poorly understood. We report a previously unrecognized mechanism whereby IL-36 promotes innate antiviral immunity in mouse and human models of herpes simplex virus-1 (HSV-1) infections. HSV-1 actively suppresses production of type I interferon (IFN); our data reveal that IL-36 overcomes this immune evasion strategy by increasing cellular sensitivity to IFN. IL-36β deficient mice display impaired IFN responses and poorly restrict viral replication in skin keratinocytes. In mouse and human keratinocytes IL-36 elicits an antiviral state driven by STAT1 and STAT2 via enhanced expression of IFNAR1 and IFNAR2 subunits of the type I IFN receptor. The degree of IFN regulatory factor 1 (IRF1) involvement is species dependent, with IRF1 playing a more prominent role in human cells. Similar mechanisms are activated by IL-1. Overall, IL-36 acts as an antiviral cytokine by potentiating type I IFN signaling and thereby upholds immune responses to viruses that limit the production of IFNs.

Herpes Simplex Virus Type 1 Interactions with the Interferon System

“…The combination of IFNγ and IFNα/β secreted at the site of infection also work synergistically both in vitro and in vivo to limit HSV-1 replication [ 151 , 152 ]. The cytokine IL36 has recently been identified as an enhancer of the type I IFN response in herpes lesions, upregulating the expression of IFNAR on keratinocytes and the subsequent activation of signal transducer and activator of transcription (STAT) 1 and STAT2 [ 153 ].…”

IL‐36 cytokines and gut immunity

“…71 Directly inhibiting the IL-36R signalling pathway has shown promising results in clinical trials; however, the blockade of IL-36R signalling could interfere with tissue repair processes and host protection against bacterial/viral/fungal infections. 15,18,20,22,24,25,34 It may, therefore, be valuable to assess methods that can neutralize individual IL-36R ligands. Todorovic et al used a small molecule high-throughput screen technique to identify compound A552, as an antagonist specific for IL-36c.…”

“…[10][11][12][13][14][15][16][17] IL-36 has been comprehensively studied in the context of skin inflammation; however, over the last decade, IL-36 cytokines have been found to have functions in viral/ bacterial/fungal infections, systemic lupus erythematosus, psoriasis, obesity and inflammatory bowel diseases. 7,10,12,15,16,[18][19][20][21][22][23][24][25] In this review, we briefly summarize the regulation of IL-36 and then discuss the current knowledge of IL-36 biology related to gut inflammation and resolution of intestinal damage. Additionally, we will talk about the limits of existing knowledge on the IL-36 functions to open prospective possibilities for research in the future.…”

Skin Viral Infections: Host Antiviral Innate Immunity and Viral Immune Evasion

“…For example, promyelocytic leukemia nuclear bodies associate with histone chaperones to capture viral DNA and block HSV replication ( 24 , 25 ). Keratinocytes were also found to release IL-1 α and IL-36 to bolster the antiviral state by acting as early alarm signals for leukocyte recruitment and increasing cellular sensitivity to type I IFN signaling, respectively ( 26 , 27 ).…”