Innate myeloid cell TNFR1 mediates first line defence against primary Mycobacterium tuberculosis infection.

Abstract

TNF is crucial for controlling Mycobacterium tuberculosis infection and understanding how will help immunomodulating the host response. Here we assessed the contribution of TNFR1 pathway from innate myeloid versus T cells. We first established the prominent role of TNFR1 in haematopoietic cells for controlling M. tuberculosis in TNFR1 KO chimera mice. Further, absence of TNFR1 specifically on myeloid cells (M-TNFR1 KO) recapitulated the uncontrolled M. tuberculosis infection seen in fully TNFR1 deficient mice, with increased bacterial burden, exacerbated lung inflammation, and rapid death. Pulmonary IL-12p40 over-expression was attributed to a prominent CD11b+ Gr1high cell population in infected M-TNFR1 KO mice. By contrast, absence of TNFR1 on T-cells did not compromise the control of M. tuberculosis infection over 6-months. Thus, the protective TNF/TNFR1 pathway essential for controlling primary M. tuberculosis infection depends on innate macrophage and neutrophil myeloid cells, while TNFR1 pathway in T cells is dispensable.

Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization

“…It clearly shows the importance of TNFα, neutrophils and macrophages in orchestrating host resistance to this infection454760. Although TNFα from both myeloid and T lymphocytes controls early and late stages of M. tuberculosis infection, respectively26, we showed recently that the TNFR1 pathway in macrophages/myeloid cells is essential for this control27, whereas soluble TNFR2 down-modulates protective immune function and reduces host resistance and survival61. Gene expression patterns in anti-TNFα antibody-treated mice pointed towards a mixed picture of pro-inflammatory M1 ( Nos2 , Ifng , Il1 ) and anti-inflammatory M2 polarization ( Arg1 , Il10 and low Il12b ) (Fig.…”

“…While TNFα from myeloid cells26 and TNFR1 on innate macrophage and neutrophil myeloid cells mediates early host resistance27, T cell-derived TNFα is essential to sustain protection during chronic mycobacterial infection in mice26. Indeed, mice deficient for TNFα or TNFR1 on myeloid cells exhibited 2 log 10 increased pulmonary bacterial load 4 weeks post- M. tuberculosis infection, as compared with wild-type mice2627, while mice deficient for TNFα of T cell origin succumbed by day 150 after M. tuberculosis infection (200–500 CFU/lung) with severe lung histopathology, necrosis and occluded alveolar space, and significantly increased, 10-fold higher pulmonary bacterial load, as compared with wild-type mice26.…”

Persistent p55TNFR expression impairs T cell responses during chronic tuberculosis and promotes reactivation

“…Collectively the data supports a mechanism by which T cell activation is regulated in a p55TNFR dependent manner during chronic M. tuberculosis infection. This is likely indirect, as we showed recently that the p55TNFR pathway in T cells is dispensable for controlling M. tuberculosis infection26. However, given our previous published data in which we demonstrated an increased p75TNFR shedding in the absence of p55TNFR resulting in reduced bioactive TNF16, we hypothesized that a similar compensationary increase in p75TNFR in the non-sheddable p55TNFR mouse strain and subsequent reduced bioactive TNF levels may be the underlying mechanism driving the observed T cell hyporesponsiveness in the p55 ∆NS mice.…”

“…TNF gene deletion21222324, p55TNFR gene deletion162526, and TNF neutralization studies2728 demonstrated TNF-TNFR signaling as critical for protective immunity against mycobacterial infections. In the absence of TNF-p55TNFR signaling, challenge of mutant mice with either attenuated M. bovis BCG29 or virulent M. tuberculosis 212425 resulted in elevated bacterial burdens, impaired granuloma structure formation and early death.…”

Identification of a TNF-α inducer MIC3 originating from the microneme of non-cystogenic, virulent Toxoplasma gondii

“…TNF-α plays several therapeutic roles within the body, including immunostimulation, resistance to tumors, and sleep regulation2650. TNF-α is also an important mediator of resistance against infectious diseases225152535455. For example, in experimental leishmaniasis, insufficient TNF-α is associated with progressive disease and death53.…”