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

Abstract

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 (IFNAR1) 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.

Biomarkers for risk of developing active tuberculosis in contacts of TB patients: a prospective cohort study

“…Chemokines such as monocyte chemoattractant protein-1 are suggested to be involved in the massive monocyte recruitment to the lung to control M. tuberculosis infection [36,37]. A role for type I interferons in the accumulation of myeloid cell populations in the lung and pulmonary recruitment of inflammatory monocytes that lead to TB disease immunopathology has also been suggested [38][39][40]. An ongoing infection with an inadequate adaptive immune response against the pathogen may explain the increased percentage of blood monocytes observed in the TB contacts in our study prior to the development of active disease.…”

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

“…These findings indicate that alveolar macrophages primarily serve as niches for, and activated macrophages predominantly serve as effectors against, Mtb. Further investigations have demonstrated that Mtb organisms primarily reside in macrophages, but can also be found in neutrophils and dendritic cells [72][73][74][75]. Direct evidence for Mtb internalization by pneumocytes in situ is scarce.…”

“…Frequencies of neutrophils in the blood of exposed individuals inversely correlate with risk of TB [81], suggesting a protective role of neutrophils. In murine models, kinetics of neutrophils in the alveolar space parallels in situ cell death of resident macrophages [82] and fine-tunes subsequent inflammatory responses [74,83,84]. The extent of alveolar macrophage death and early tissue damage modulates preadaptive neutrophilic infiltration of the alveolar space [74,82].…”

“…In murine models, kinetics of neutrophils in the alveolar space parallels in situ cell death of resident macrophages [82] and fine-tunes subsequent inflammatory responses [74,83,84]. The extent of alveolar macrophage death and early tissue damage modulates preadaptive neutrophilic infiltration of the alveolar space [74,82]. Signaling through IFN-alpha receptor-1 (IFNAR1) promotes bacillary replication and death of alveolar macrophages [74].…”

“…The extent of alveolar macrophage death and early tissue damage modulates preadaptive neutrophilic infiltration of the alveolar space [74,82]. Signaling through IFN-alpha receptor-1 (IFNAR1) promotes bacillary replication and death of alveolar macrophages [74]. Although the link between the type of alarmins or death signals and neutrophilic responses is still elusive, it has been demonstrated that neutrophil chemotaxis is directed by local gradients of CXCR2 agonists [83,85,86].…”