Type I IFN signaling triggers immunopathology in tuberculosis‐susceptible mice by modulating lung phagocyte dynamics

May 1, 2014European journal of immunology

Type I Interferon signaling may cause harmful immune responses in tuberculosis-prone mice by changing lung infection-fighting cell behavior

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Abstract

Mice lacking the receptor for interferon type I () were protected from death following infection with Mycobacterium tuberculosis.

IFNAR1 signaling did not influence T-cell responses but significantly affected the movement of inflammatory monocytes and neutrophils to the lungs.
The signaling pathway involved IFNAR1 on both immune and tissue-resident cells.
Increased susceptibility to tuberculosis was linked to enhanced replication of Mtb and localized cell death.
Accumulation of neutrophils in the alveoli was driven by the chemokines CXCL5 and CXCL1.
Early removal of neutrophils improved survival rates in TB-susceptible mice to levels seen in mice without IFNAR1.

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General interest in the biological functions of IFN type I in Mycobacterium tuberculosis (Mtb) infection increased after the recent identification of a distinct IFN gene expression signature in tuberculosis (TB) patients. Here, we demonstrate that TB-susceptible mice lacking the receptor for IFN I () were protected from death upon aerogenic infection with Mtb. Using this experimental model to mimic primary progressive pulmonary TB, we dissected the immune processes affected by IFN I. IFNAR1 signaling did not affect T-cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung. This process was orchestrated by IFNAR1 expressed on both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by augmented Mtb replication and in situ death events, along with CXCL5/CXCL1-driven accumulation of neutrophils in alveoli, followed by the discrete compartmentalization of Mtb in lung phagocytes. Early depletion of neutrophils rescued TB-susceptible mice to levels observed in mice lacking IFNAR1. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to fatal immunopathology. These data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB and form a basis for understanding the complex roles of IFN I in chronic inflammation.

Key numbers

40 days

Survival Rate Improvement

Survival duration of TB-susceptible mice post-infection.

25–29

Bacterial Burden Reduction

Bacterial colony counts in lungs at day 21 post-infection.

9–13

Inflammatory Mediators

Cytokine concentrations measured in lung homogenates at 21 days post-infection.

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Abstract

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