TNFRp75‐dependent immune regulation of alveolar macrophages and neutrophils during early Mycobacterium tuberculosis and Mycobacterium bovis BCG infection

Abstract

SummaryTNF signalling through TNFRp55 and TNFRp75, and receptor shedding is important for immune activation and regulation. TNFRp75 deficiency leads to improved control of Mycobacterium tuberculosis (M. tuberculosis) infection, but the effects of early innate immune events in this process are unclear. We investigated the role of TNFRp75 on cell activation and apoptosis of alveolar macrophages and neutrophils during M. tuberculosis and M. bovis BCG infection. We found increased microbicidal activity against M. tuberculosis occurred independently of IFNy and NO generation, and displayed an inverse correlation with alveolar macrophages (AMs) apoptosis. Both M. tuberculosis and M. bovis BCG induced higher expression of MHC‐II in TNFRp75−/− AMs; however, M bovis BCG infection did not alter AM apoptosis in the absence of TNFRp75. Pulmonary concentrations of CCL2, CCL3 and IL‐1β were increased in TNFRp75−/− mice during M, bovis BCG infection, but had no effect on neutrophil responses. Thus, TNFRp75‐dependent regulation of mycobacterial replication is virulence dependent and occurs independently of early alveolar macrophage apoptosis and neutrophil responses.

Allele-dependent interaction of LRRK2 and NOD2 in leprosy

“…In humans, primates and mice, TNF plays a critical role in containment of chronic and latent M . tuberculosis infection [ 73 ]. Accordingly, anti-TNF immunotherapy, which is used for the treatment of autoimmune and chronic inflammatory diseases, disrupts effective immunity against M .…”

“…TNF is a key pro-inflammatory cytokine in mycobacterial infections that triggers granuloma formation while inhibiting mycobacterial growth [72]. In humans, primates and mice, TNF plays a critical role in containment of chronic and latent M. tuberculosis infection [73]. Accordingly, anti-TNF immunotherapy, which is used for the treatment of autoimmune and chronic inflammatory diseases, disrupts effective immunity against M. tuberculosis and therefore increases the risk of latent TB reactivation [74,75].…”

Virulence Factors of Mycobacterium tuberculosis as Modulators of Cell Death Mechanisms

“…Soluble TNFR2 may inhibit induced apoptosis during the Mtb infection. However, this phenomenon was not observed during the BCG infection, suggesting that the impact of TNFR2 may be modulated by mycobacterial virulence [ 67 , 68 ]. In macrophages, TNF-induced ROS production increases the associated kinases, c-Abl, ASK1, and p38, leading to FLIP (FLICE-inhibitory protein) phosphorylation, promoting its interaction with the ubiquitin E3 ligase c-Cbl.…”

Transmembrane TNF and Its Receptors TNFR1 and TNFR2 in Mycobacterial Infections

“…A particular inverse correlation has been found between mycobacteria virulence and apoptosis induction [ 130 ]. In this regard, recently it has been reported that TNFR2 increases microbicidal activity against M. tuberculosis independently of IFNγ and nitric oxide, and it displays an inverse correlation with macrophages apoptosis, but this apoptosis is not observed under BCG infection, suggesting that regulation of apoptosis and mycobacterial replication by TNFR2 is a virulence dependent pathway [ 131 ]. However, beyond virulence, several factors are involved with the induction or inhibition of apoptosis during mycobacterial infection, for instance, strain phenotype, stage of infection, and cell condition may interfere.…”