Macrophage coordination of interferon lambda driven inflammation — ASN Events
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  2. Poster Session Three
  3. Macrophage coordination of interferon lambda driven inflammation

Macrophage coordination of interferon lambda driven inflammation (#354)

Scott Read 1 , Ratna Wijaya 1 , Mehdi Ramezani Moghadam 1 , Chris Liddle 1 , Mark Douglas 1 , David Booth 2 , Jacob George 1 , Golo Ahlenstiel 1 3
  1. Storr Liver Centre, Westmead Institute for Medical Research, Westmead, NSW, Australia
  2. Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
  3. Blacktown Clinical School, Western Sydney University, Blacktown, NSW, Australia

Background. Interferon lambdas (IFN-λs) are potent antiviral cytokines that have become implicated in numerous chronic diseases including lupus, liver cirrhosis and inflammatory bowel disease. Despite the strong association of IFN-λ with chronic inflammation, surprisingly little is known about how IFN-λ drives this response. Intriguingly, we have demonstrated that circulating monocytes are unresponsive to IFN-λs while tissue macrophages are highly sensitive. Immune cells central to the innate (natural killer (NK) cell) and adaptive (B and T cells) immune responses are unresponsive to IFN-λs, suggesting that macrophages can coordinate local inflammation in response to IFN-λ.

Methods. CD14+ blood monocytes were magnetically isolated and differentiated into macrophages using M-CSF (M2) or GM-CSF (M1) alone, or in the presence of IFN-λ3. Macrophage inflammatory gene expression and cytokine/chemokine secretion were measured by RNA sequencing, qPCR and ELISA. Flow cytometry was used to measure macrophage capacity to induce apoptosis of virus infected cells and phagocytosis of bacteria as well as IFN-λ driven immune cell migration and subsequent activation.

Results. Pro-inflammatory macrophages differentiated in GM-CSF were significantly more responsive to IFN-λ3, up-regulating numerous activation markers, inflammatory cytokines and chemokines. Furthermore, incubation with IFN-λ3 exacerbated the inflammatory response to TLR ligands LPS (TLR4), polyI:C (TLR3, RIG-I) and zymosan (TLR2, Dectin-1). Functionally, macrophages differentiated in the presence of IFN-λ3 stimulated T, NK and NKT cell chemotaxis and increased subsequent NK cell cytotoxicity. Additionally, macrophage mediated apoptosis of hepatitis C virus (JFH-1 strain) infected hepatocytes was increased by IFN-λ3, as was bacterial phagocytosis.

Discussion. These data demonstrate that IFN-λs enhance the macrophage inflammatory response to foreign pathogens by stimulating self and non-self immune activation. These data provide relevant new mechanisms, and thus identifies new targets for therapeutic intervention in  chronic diseases in which IFN-λs are implicated.

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