Abstract:
Alveolar 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, and Ifit3. 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.
摘要:
肺泡巨噬细胞(AM)是下气道驻留的骨髓细胞,是最早对吸入病原体作出反应的细胞之一。这里,我们询问AM对病原体相关分子模式(PAMPs)的先天感知,并确定与其他巨噬细胞相比,AM对低剂量LPS的反应降低,用TNF测量,IL-6,Ifnb,还有Ifit3.我们发现对低剂量LPS的反应降低与TLR4和CD14表面表达最小相关。尽管TLR4有足够的内部表达。此外,我们发现,由于转录因子c-Maf的低表达,AMs不响应多种PAMPs产生IL-10,而IL-10产生的缺乏有助于增强I型IFN的促炎反应。我们的发现表明,AMs对LPS具有细胞内在的抑制作用,通过I型IFN暴露增强。这些数据暗示了AM可能对细菌感染的前哨反应降低或增强的情况。
结论:肺泡巨噬细胞(AMs)由于TLR4和CD14的最小表面表达而不会对低剂量LPS产生TNF或IL-6。缺乏AMIL-10的产生依赖于低c-Maf表达外源c-Maf表达增加AMIL-10的产生IFNβAMTNF和IL-6对低剂量LPS的反应,这取决于IL-10的缺乏。