IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia

Abstract

Influenza virus causes a respiratory disease in human that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL-36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines is poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36α mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36α but not IL-36γ is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36α was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection.

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

“…Signaling by IL-36γ and IL-36R has previously been shown to increase chemokine levels and promote leukocyte recruitment in both the skin and lungs [14, 62–64]. Indeed, we observed that IL-36γ exposure elicited significantly increased levels of the chemokines CCL20 and KC measured in both FRT tissue and vaginal lavages 4h following treatment (Fig.…”

“…IL-36α, - β, and -γ are all expressed in nonhematopoietic cells, including keratinocytes and mucosal epithelial cells, but are induced in response to different inflammatory stimuli [23]. For example, IL-36α and IL-36γ have been shown to be robustly induced in bronchial epithelial cells in response to microbial products, bacterial infection, and viral infection, suggesting that the IL-36 cytokines may play an important role in epithelial host defense [14, 18, 19, 24, 25]. Indeed, IL-36γ −/− mice exhibited delayed clearance of Streptococcus pneumoniae and Klebsiella pneumoniae in lung infections, decreased Th1 and Th17 cytokine levels, and increased mortality [18].…”

“…In Mycobacterium tuberculosis infections, IL-36γ promotes the production of AMPs that limit bacterial growth [13, 26]. In another study, it was found that IL-36R signaling and IL-36α promoted the production of immune mediators and increased influx of neutrophils and monocytes in response to influenza virus infection in the lungs, indicating that the IL-36 cytokines may have distinct functions in response to specific inflammatory stimuli[14]. It has been well documented that the viral RNA mimic poly(I:C) induces IL-36γ, further demonstrating that IL-36γ may play a role in host antiviral defense mechanisms [12, 27, 28].…”

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

“…Production of antimicrobial peptides provides additional means to inhibit viral replication and modulate antiviral immune responses, for example, by triggering virus aggregation or trapping, viral envelope disruption, and enhanced IFN-b production (118,119). In agreement with this, an in vivo role for IL-36a was demonstrated in a murine model of influenza pneumonia (120). However, given the apparent redundancy in how the IL-1s and IL-36s activate cells ( Fig.…”

“…Hence, in combination with IL-1a, the IL-36s may promote immunity against these pathogens to clear or control the infections over time. Although this review is focused on skin immunity, it is noteworthy and in agreement with this hypothesis that IL-36a plays an essential role in initiating immune responses against influenza (120). The influenza protein NS1 (nonstructural protein 1) blocks NLRP3 function (134,135), similar to inflammasome inhibition by other viruses, as described above.…”