Recruitment and training of alveolar macrophages after pneumococcal pneumonia.

Emad I Arafa,Alicia K Wooten,Lee J Quinton,Matthew R Jones,Filiz T Korkmaz,Wesley N Goltry,Anna C Belkina,Antoine Guillon,Anukul T Shenoy,Elim Na,Kimberly A Barker,Carolina Lyon De Ana,E Camilla Forsberg,Neelou S Etesami,Joseph P Mizgerd,Christine V Odom,Ian M.C Martin

doi:10.1172/jci.insight.150239

Abstract

Recovery from pneumococcal pneumonia remodels the pool of alveolar macrophages so that they exhibit new surface marker profiles, transcriptomes, metabolomes, and responses to infection. Mechanisms mediating alveolar macrophage phenotypes after pneumococcal pneumonia have not been delineated. IFN-γ and its receptor on alveolar macrophages were essential for certain, but not all, aspects of the remodeled alveolar macrophage phenotype. IFN-γ was produced by CD4+ T cells plus other cells, and CD4+ cell depletion did not prevent alveolar macrophage remodeling. In mice infected or recovering from pneumococcus, monocytes were recruited to the lungs, and the monocyte-derived macrophages developed characteristics of alveolar macrophages. CCR2 mediated the early monocyte recruitment but was not essential to the development of the remodeled alveolar macrophage phenotype. Lineage tracing demonstrated that recovery from pneumococcal pneumonias converted the pool of alveolar macrophages from being primarily of embryonic origin to being primarily of adult hematopoietic stem cell origin. Alveolar macrophages of either origin demonstrated similar remodeled phenotypes, suggesting that ontogeny did not dictate phenotype. Our data reveal that the remodeled alveolar macrophage phenotype in lungs recovered from pneumococcal pneumonia results from a combination of new recruitment plus training of both the original cells and the new recruits.

Highlights

Lung infections are a leading cause of morbidity and mortality [1,2,3,4,5]
Numbers and surface marker phenotypes of alveolar macrophages fluctuate after infection Naturally acquired immune defense against pneumococcal pneumonia can be achieved in mice by administering two self-limiting respiratory infections with Streptococcus pneumoniae serotype 19F (Sp19F) spaced one week apart followed by a month of recovery, after which the mice demonstrate a long-lasting heterotypic protection that involves remodeled AM of unknown sources [21,23,24,25,26]
To determine whether and how AM numbers change during the infection history that establishes heterotypic protection against pneumococcal pneumonia [21,23,24,25,26], naïve mice were ushered through serial infections and at designated time-points lungs were collected and digested to single cell suspensions for flow cytometry

Summary

Introduction

Microbes that enter the air spaces of the lung encounter alveolar macrophages (AM), which function as sentinels and immune modulators. These cells protect the lung by clearing microbial and non-microbial agents, initiating pulmonary inflammation, and contributing to resolution and repair [6,7]. AM can arise from either of two disparate origins They derive from embryonic sources, including yolk sac precursors and fetal liver hematopoiesis [8,9,10,11]. Factors that kill AM can more rapidly convert the AM pool to becoming dominated by monocyte-derived cells from adult hematopoiesis [12,13,14]. The AM of fetal origin and of adult hematopoietic origin are largely similar but not identical to each other when compared across multiple characteristics including surface markers, gene expression, and functional activities [18,19,20]

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Results

Conclusion