Modeling the immune rheostat of macrophages in the lung in response to infection

Day, Judy; Friedman, Avner; Schlesinger, Larry S.

doi:10.1073/pnas.0904846106

Cited by 127 publications

(81 citation statements)

References 55 publications

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“…M 1 polarization timing and magnitude for an entire granuloma are significant factors in containing the infection. Our predictions are in line with those of Day et al (111), where they predicted switching times of ϳ50 days. Here we showed how stronger M 1 polarization 2 to 3 months postinfection is necessary to drive a stronger protective immune response that is better at containing bacterial proliferation.…”

Section: Discussionsupporting

confidence: 93%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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c Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-B signal activation intervals. These results suggest that the dynamics of NF-B signaling is a viable therapeutic target to promote M 1 polarization early during infection and to improve outcome.

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Section: Discussionsupporting

confidence: 93%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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“…Traditionally, contrasting phenotypes is accomplished through data analysis, from which speculative mechanisms explaining differences are inferred (Gingles et al, 2001; Lommatzsch et al, 2007; Prince et al, 2006; Ashman and Papadimitriou, 1992; Day et al, 2009; Ludewick et al, 2011; Buckley et al, 1997). Our ensemble-based approach determines putative mechanisms a priori , and quantifies their relative importance in explaining various phenotypes through distributional differences in phenotype-specific ensemble.…”

Section: Discussionmentioning

confidence: 99%

A mathematical model of intrahost pneumococcal pneumonia infection dynamics in murine strains

Mochan

Swigon

Ermentrout

et al. 2014

Journal of Theoretical Biology

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The seriousness of pneumococcal pneumonia in mouse models has been shown to depend both on bacterial serotype and murine strain. We here present a simple ordinary differential equation model of the intrahost immune response to bacterial pneumonia that is capable of capturing diverse experimentally determined responses of various murine strains. We discuss the main causes of such differences while accounting for the uncertainty in the estimation of model parameters. We model the bacterial population in both the lungs and blood, the cellular death caused by the infection, and the activation and immigration of phagocytes to the infected tissue. The ensemble model suggests that inter-strain differences in response to streptococcus pneumonia inoculation reside in the strength of nonspecific immune response and the rate of extrapulmonary phagocytosis.

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“…Lung-resident macrophages are another important regulator of pulmonary innate immunity, determining whether to initiate certain inflammatory cascades or remain quiescent in response to pathogenic or cellular damage (Day, et al, 2009). These cells are notoriously poor stimulators of T cell proliferation, and have been described under a variety of conditions to be regulatory in nature (Lambrecht, 2006).…”

Section: Innate and Adaptive Immunity In The Pathogenesis Of Emphymentioning

confidence: 99%

Immune-mediated inflammation in the pathogenesis of emphysema: insights from mouse models

2017

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The cellular mechanisms that result in the initiation and progression of emphysema are clearly complex. A growing body of human data combined with discoveries from mouse models utilizing cigarette smoke exposure or protease administration have improved our understanding of emphysema development by implicating specific cell types that may be important for the pathophysiology of COPD. The most important aspects of emphysematous damage appear to be oxidative or protease stress and sustained macrophage activation and infiltration of other immune cells leading to epithelial damage and cell death. Despite the identification of these associated processes and cell types in many experimental studies, the reasons why cigarette smoke and other pollutants result in unremitting damage instead of injury resolution are still uncertain. We propose an important role for macrophages in the sequence of events that lead and maintain this chronic tissue pathologic process in emphysema. This model involves chronic activation of macrophage subtypes that precludes proper healing of the lung. Further elucidation of the cross-talk between epithelial cells that release damage-associated signals and the cellular immune effectors that respond to these cues is a critical step in the development of novel therapeutics that can restore proper lung structure and function to those afflicted with emphysema.

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Modeling the immune rheostat of macrophages in the lung in response to infection

Cited by 127 publications

References 55 publications

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

A mathematical model of intrahost pneumococcal pneumonia infection dynamics in murine strains

Immune-mediated inflammation in the pathogenesis of emphysema: insights from mouse models

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