Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection

Abstract

Despite the prevalence and clinical importance of influenza, its long-term effect on lung immunity is unclear. Here we describe that following viral clearance and clinical recovery, at one month post-influenza, mice are better protected from Streptococcus pneumoniae infection due to a population of monocyte-derived alveolar macrophages (AMs) which produce increased IL-6. Influenza-induced monocyte-derived AMs have a surface phenotype similar to resident AMs but display a unique functional, transcriptional and epigenetic profile which is distinct from resident AMs. In contrast, influenza-experienced resident AMs remain largely similar to naive AMs. Thus, influenza changes the composition of the AM population to provide prolonged antibacterial protection. Monocyte-derived AMs persist over time but lose their protective profile. Our results help to understand how transient respiratory infections, a common occurrence in human life, can constantly alter lung immunity by contributing monocyte-derived, recruited cells to the AM population.

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

“…For 25 example, the loss of MHC class I molecules on myeloid cells is not only seen in COPD, it is also described in cancer (Noy and Pollard, 2014) and in influenza (Koutsakos et al, 2019). Similarly, the increase of the mono-like macrophage cell state as a hallmark for cell influx from the systemic circulation will also be seen in other pathophysiological situations of the lung, for example, acute infections such as pneumonia (Goto et al, 2004) or influenza infection (Aegerter et al, 2020). In contrast, the combination of these changes together with the changes observed in lipid metabolism or the COPD AM signature also observed in peripheral blood monocytes are good starting points for future biomarker development for COPD diagnostics and outcome prediction.…”

Influenza-induced activation of recruited alveolar macrophages during the early inflammatory phase drives lung injury and lethality

“…We also characterized the time course by which macrophages respond to IAV infection. Previous studies have compared macrophages at baseline and following IAV infection [9,36,37]. However, our results suggest that macrophages engage in different functions depending on the phase of IAV response.…”

Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder

“…In the steady state, tissue-resident macrophages can self-maintain locally by proliferation, with minimal input of circulating monocytes (Hashimoto et al, 2013;Merad et al, 2002). By contrast, under inflammatory conditions, resident macrophages are often replaced by monocyte-derived macrophages (Aegerter et al, 2020;Bleriot et al, 2015;Merad et al, 2002;Misharin et al, 2017). Monocytes will differentiate into self-renewing functional macrophages if the endogenous tissue resident macrophages are depleted or are absent van de Laar et al, 2016).…”

“…Alveolar macrophages of mice infected with influenza virus are replaced by pro-inflammatory monocyte-derived macrophages. At 30 days post-infection, influenza-infected mice have more alveolar macrophages and increased production of IL-6 when challenged with S. pneumoniae compared to mock-infected mice, leading to less death (Aegerter et al, 2020). Although mechanisms regulating the phenotype of monocyte-derived macrophages are not known, the time of residency in the tissue and the nature of subsequent insults likely influence these cells.…”

“…Indeed, the longer that recruited macrophages reside in tissue, the more similar they become to tissueresident macrophages and no longer provide enhanced protection to subsequent tissue injury (Aegerter et al, 2020;Misharin et al, 2017). In contrast to these studies in the lung, we found that elimination of macrophages, including those recruited during primary infection, led to improved bacterial clearance during secondary challenge, although it is not clear what the long-term consequences on bladder homeostasis might be when a more inflammatory type 1 immune response arises during infection.…”