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Updated: Jun 24, 2025
Polarization of M1 and M2 Human Monocyte-Derived Cells and Analysis with Flow Cytometry upon Mycobacterium tuberculosis Infection
Published on: September 18, 2020
Type I interferon exacerbates Mycobacterium tuberculosis induced human macrophage death
Angela M Lee1,2, Carl F Nathan3,4
1Department of Microbiology & Immunology, Weill Cornell Medicine, New York, NY, 10065, USA.
Abstract:
Type I interferons (IFN-I) are implicated in exacerbation of tuberculosis (TB), but the mechanisms are unclear. Mouse macrophages infected with Mycobacterium tuberculosis (Mtb) produce IFN-I, which contributes to their death. Here we investigate whether the same is true for human monocyte-derived macrophages (MDM). MDM prepared by a conventional method markedly upregulate interferon-stimulated genes (ISGs) upon Mtb infection, while MDM prepared to better restrict Mtb do so much less. A mixture of antibodies inhibiting IFN-I signaling prevents ISG induction. Surprisingly, secreted IFN-I are undetectable until nearly two days after ISG induction. These same antibodies do not diminish Mtb-infected MDM death. MDM induce ISGs in response to picogram/mL levels of exogenous IFN-I while depleting similar quantities from the medium. Exogenous IFN-I increase the proportion of dead MDM. We speculate that Mtb-infected MDM produce and respond to minute levels of IFN-I, and that only some of the resultant signaling is susceptible to neutralizing antibodies. Many types of cells may secrete IFN-I in patients with TB, where IFN-I is likely to promote the death of infected macrophages.
Insights
Tuberculosis-infected human macrophages produce type I interferons (IFN-I), triggering cell death. Inhibiting IFN-I signaling reduces gene induction but not macrophage death, suggesting complex mechanisms in TB pathogenesis.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Type I interferons (IFN-I) are linked to tuberculosis (TB) exacerbation, but the underlying mechanisms remain unclear.
- Previous studies in mice indicated that IFN-I produced by Mycobacterium tuberculosis (Mtb)-infected macrophages contributes to cell death.
Purpose of the Study:
- To investigate whether Mtb-infected human monocyte-derived macrophages (MDM) also produce IFN-I and if it contributes to their death.
- To elucidate the role of IFN-I signaling in the response of human MDM to Mtb infection.
Main Methods:
- Human MDM were infected with Mtb, and the expression of interferon-stimulated genes (ISGs) was analyzed.
- Antibodies inhibiting IFN-I signaling were used to assess their impact on ISG induction and MDM death.
- Quantification of secreted IFN-I and assessment of MDM response to exogenous IFN-I were performed.
Main Results:
- Mtb-infected human MDM markedly upregulated ISGs, particularly when prepared conventionally.
- IFN-I signaling inhibition prevented ISG induction but did not reduce Mtb-infected MDM death.
- Secreted IFN-I was undetectable until late stages, despite early ISG induction.
- Exogenous IFN-I induced ISG expression and increased MDM death.
Conclusions:
- Mtb-infected human MDM produce and respond to low levels of IFN-I, contributing to ISG induction and cell death.
- The observed IFN-I signaling is complex, with only partial susceptibility to neutralizing antibodies.
- IFN-I likely promotes infected macrophage death in TB patients, potentially involving various cell types.
