Timed Action of IL-27 Protects from Immunopathology while Preserving Defense in Influenza

Abstract

Infection with influenza virus can result in massive pulmonary infiltration and potentially fatal immunopathology. Understanding the endogenous mechanisms that control immunopathology could provide a key to novel adjunct therapies for this disease. Here we show that the cytokine IL-27 plays a crucial role in protection from exaggerated inflammation during influenza virus infection. Using Il-27ra −/− mice, IL-27 was found to limit immunopathology, neutrophil accumulation, and dampened TH1 or TH17 responses via IL-10–dependent and -independent pathways. Accordingly, the absence of IL-27 signals resulted in a more severe disease course and in diminished survival without impacting viral loads. Consistent with the delayed expression of endogenous Il-27p28 during influenza, systemic treatment with recombinant IL-27 starting at the peak of virus load resulted in a major amelioration of lung pathology, strongly reduced leukocyte infiltration and improved survival without affecting viral clearance. In contrast, early application of IL-27 impaired virus clearance and worsened disease. These findings demonstrate the importance of IL-27 for the physiological control of immunopathology and the potential value of well-timed IL-27 application to treat life-threatening inflammation during lung infection.

The Immunobiology of Interleukin-27

“…Thus, MRL/lpr mice that lack IL-27Rα have increased numbers of dermal mast cells (147), and in a model of passive cutaneous anaphylaxis, or when challenged with a helminth, Il-27rα −/− mice have elevated circulating levels of mast cell protease (12). Enhanced neutrophil activity has been a common characteristic of the absence of IL-27 in multiple experimental systems, including models of peritoneal sepsis (148) and infection with respiratory syncytial virus (RSV) (149,150); however, administering IL-27 to mice acutely infected with influenza reduced neutrophil accumulation and was associated with impaired viral clearance (20). Indeed, in mice infected with LCMV, the absence of IL-27Rα results in increased early viremia that may be due to a role of innate cells, but whether this is related to the situation seen with influenza is unclear (132).…”

“…The discovery that WSX-1/TCCR was part of the receptor for IL-27, and that IL-27 activated STAT1 and T-bet to promote responsiveness to IL-12 and production of IFN-γ, provided a mechanism to explain how IL-27 could promote Th1 cells (1,(5)(6)(7)(8). However, when Il27ra −/− mice were challenged with different classes of viral, bacterial, or parasitic pathogens (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), or utilized in models of tissue-specific autoimmunity (24)(25)(26)(27)(28)(29)(30)(31), these experiments identified a role for IL-27 as a negative regulator of T cell responses. Since then, multiple studies have shown that IL-27 can antagonize Th1, Th2, Th9, and Th17 responses, but it has been difficult to reconcile these inhibitory activities with the ability of IL-27 to promote T cell growth and survival, and, under certain circumstances, effector T cell functions (1,32).…”

The Roles of Type I Interferon in Bacterial Infection

“…Downregulation of the proinflammatory response is essential to protect against tissue damage induced mortality as observed during Escherichia coli sepsis (Sewnath et al, 2001), but it is detrimental to the clearance of other bacterial infections (Auerbuch et al, 2004; Di Paolo et al, 2015; Mayer-Barber et al, 2014; McNab et al, 2014). Similarly, IL-27 protects against tissue damage during acute influenza infection (Liu et al, 2014), but compromises the host response to both secondary (Cao et al, 2014; Robinson et al, 2015) and chronic bacterial infections (Teles et al, 2015). The delicate balance between proinflammatory and anti-inflammatory responses is further illustrated by chemokine recruitment.…”

Interleukin-27 as a Novel Therapy for Inflammatory Bowel Disease

“…In support of this finding, IL-27 treatment of mice in the late stage of influenza infection decreased both clinical signs of disease and lung histopathology scores without reducing clearance of the virus. 32 This improvement in pathology corresponded to significantly lower pulmonary infiltrates of both neutrophils and monocytes, which were proposed by the authors to be due to IL-27-mediated suppression of the chemokines CXCL1, CCL5, and CCL4. However, in sharp contrast to this beneficial function of IL-27, the reduction of neutrophil and monocyte infiltrates due to administration of IL-27 early in influenza infection prevented viral clearance and worsened the clinical signs of disease.…”

“…32,33 Mice with genetic deletion of IL-27Rα had more severe pulmonary histopathology and greater mortality following influenza infection than wild type mice, suggesting that IL-27 signaling is protective in influenza infection. In support of this finding, IL-27 treatment of mice in the late stage of influenza infection decreased both clinical signs of disease and lung histopathology scores without reducing clearance of the virus.…”