Early IL-1 Signaling Promotes iBALT Induction after Influenza Virus Infection

Katrijn Neyt,Corine H Geurtsvankessel,Hamida Hammad,Kim Deswarte,Bart N Lambrecht

doi:10.3389/fimmu.2016.00312

Abstract

Inducible bronchus-associated lymphoid tissue (iBALT) is a long lasting tertiary lymphoid tissue that can be induced following influenza A virus (IAV) infection. Previous studies have shown that iBALT structures containing germinal center (GC) B cells protect against repeated infection by contributing locally to the cellular and humoral immune response. If we are to exploit this in vaccination strategies, we need a better understanding on how iBALT structures are induced. One hypothesis is that the strength of the initial innate response dictates induction of iBALT. In the present study, we investigated the role of interleukin (IL)-1 and IL-1R signaling on iBALT formation. Mice lacking the IL-1R had a delayed viral clearance and, thus, a prolonged exposure to viral replication, leading to increased disease severity, compared to wild-type mice. Contradictorily, iBALT formation following clearance of the virus was heavily compromised in Il1r1−/− mice. Quantification of gene induction after IAV infection demonstrated induction of IL-1α and to a much lesser extent of IL-1β. Administration of recombinant IL-1α to the lungs of wild-type mice, early but not late, after IAV infection led to more pronounced iBALT formation and an increased amount of GC B cells in the lungs. Bone marrow chimeric mice identified the stromal compartment as the crucial IL-1 responsive cell for iBALT induction. Mechanistically, Q-PCR analysis of lung homogenates revealed a strongly diminished production of CXCL13, a B cell-attracting chemokine, in Il1r−/− mice during the early innate phase of IAV infection. These experiments demonstrate that appropriate innate IL-1α–IL-1R signaling is necessary for IAV clearance and at the same time instructs the formation of organized tertiary lymphoid tissues through induction of CXCL13 early after infection. These findings are discussed in the light of recent insights on the pathogenesis of tertiary lymphoid organ formation in the lung in various diseases where the IL-1 axis is hyperactive, such as rheumatoid arthritis and COPD.

Highlights

Influenza A virus (IAV) is a respiratory pathogen that causes seasonal or pandemic outbreaks with severe outcome in elderly and immune compromised patients
To assess the immune response to IAV infection in mice lacking signaling via IL-1R, we infected Il1r1−/− mice and monitored weight loss and viral load in the lungs
The IL-1 axis has been described previously to be responsible for inflammatory pathology in the lung, resulting in increased mortality, increased viral titers, and neutrophil recruitment following IAV infection [7]

Summary

Introduction

Influenza A virus (IAV) is a respiratory pathogen that causes seasonal or pandemic outbreaks with severe outcome in elderly and immune compromised patients. Epithelial cells are the first target cells for IAV infection [1, 2] and coordinate the innate immune defense to prevent spreading of the virus, via production of type I interferons (IFNs). Infection with IAV leads to activation of the Nlrp inflammasome in a process requiring the type I IFN-induced RNAse L/OAS system, while the virus actively suppresses IL-1β production and Nlrp activation via the NS1 protein [4,5,6]. It promotes survival by killing virus-infected cells, clearing debris, and alarming the adaptive immune response. The outcome of genetic deficiency of key components in IL-1 generation or signaling has been very different depending on the severity of the IAV infection [2, 9, 11]

Methods

Results

Conclusion