Interferon Regulatory Factor 8-Deficiency Determines Massive Neutrophil Recruitment but T Cell Defect in Fast Growing Granulomas during Tuberculosis

Abstract

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions.

IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes

“…Autophagy is a major mechanism by which MΦs eliminate intracellular bacteria, such as M. tuberculosis, Salmonella, and Listeria 6 , 10 , 41 . Previous studies showed that IRF8 is essential for controlling infection of the above bacteria 22 - 26 . However, it has not been clear whether IRF8 employs autophagy to confer protection.…”

“…Our results are consistent with this early study and provide deeper insight into the mechanism by which IRF8 confers resistance to the bacteria. In a similar context, it has been shown that IRF8 is essential for controlling infection by other bacteria, including M. tuberculosis: mutations in Irf8 are associated with increased susceptibility to Mycobacteria infection in mice and humans 24 - 26 . However, underlying molecular mechanisms have not been fully clarified.…”

“…IRF8 is induced by IFNγ plus TLRs in MΦs and stimulates genes important for host defense, including type I IFNs, promoting production of reactive oxygen species and nitric oxide 20 , 21 . IRF8 is essential for innate resistance against intracellular bacteria, including M. tuberculosis, M. Bovis (BCG), Salmonella and Listeria, although underlying mechanisms have not been fully understood 22 - 26 .…”

A multidisciplinary study usingin vivotumor models and microfluidic cell-on-chip approach to explore the cross-talk between cancer and immune cells

“…in vivo models and a novel microfluidic cell-on-chip strategy. In addition, as a growing number of reports have suggested an important role for IRF-8 in immunity (Aliberti et al, 2003;Mattei et al, 2006;Rocca et al, 2013;Schiavoni et al, 2002Schiavoni et al, , 2004Tsujimura et al, 2003), and considering that IRF-8 KO mice are endowed with a functionally impaired immune response, this allowed the current studies to also examine the possibility that IRF-8 could have a role in the immune responses against cancer and also potentially in any cross-talk between the target and effector cells. Accordingly, the current study utilized an IRF-8 KO in vivo model to provide evidence this transcription factor was key to ensuring an effective immune response against melanoma progression.…”

Insights on the crosstalk between dendritic cells and helper T cells in novel genetic etiology for mendelian susceptible mycobacterial disease

“…23 Importantly, it has been previously reported that IRF8-deficiency determines the immune cells recruitment in granuloma during Tuberculosis. 24 Along these lines, it would be interesting to further study the growth of the bacteria and as to how the granuloma structure could be affected in SPPL2a-deficient patients. Herein, these data open a new research branch for the elucidation of novel mechanisms developed by pathogens to evade the IFN-γ response, which could contribute to the susceptibility to the infections by major virulent agents, such as Mycobacterium tuberculosis.…”