Absence of c-Maf and IL-10 enables Type I IFN enhancement of innate responses to low-dose LPS in alveolar macrophages

Abstract

SUMMARYAlveolar macrophages (AMs) are lower-airway resident myeloid cells and are among the first to respond to inhaled pathogens. Here, we interrogate AM innate sensing to Pathogen Associated Molecular Patterns (PAMPs) and determine AMs have decreased responses to low- dose LPS compared to other macrophages, as measured by TNF, IL-6,Ifnb, andIfit3. We find the reduced response to low-dose LPS correlates with minimal TLR4 and CD14 surface expression, despite sufficient internal expression of TLR4. Additionally, we find that AMs do not produce IL-10 in response to a variety of PAMPs due to low expression of transcription factor c- Maf and that lack of IL-10 production contributes to an enhancement of pro-inflammatory responses by Type I IFN. Our findings demonstrate that AMs have cell-intrinsic dampened responses to LPS, which is enhanced by type I IFN exposure. These data implicate conditions where AMs may have reduced or enhanced sentinel responses to bacterial infections.HIGHLIGHTSAlveolar macrophages (AMs) do not produce TNF or IL-6 in response to low-dose LPS due to minimal surface expression of TLR4 and CD14Lack of AM IL-10 production is dependent on low c-Maf expressionExogenous c-Maf expression increases AM IL-10 productionIFNβ enhances AM TNF and IL-6 responses to low-dose LPS and this is dependent on a lack of IL-10