Lethal Granuloma Disintegration in Mycobacteria-Infected TNFRp55−/− Mice Is Dependent on T Cells and IL-12

Abstract

Genetically susceptible, TNFRp55 gene-deficient (TNFRp55−/−) mice succumb to infection with Mycobacterium avium. Before their death, M. avium-infected TNFRp55−/− mice develop granulomatous lesions that, in contrast to granulomas in wild-type syngeneic mice, undergo acute disintegration. To determine the factors involved in these events, we depleted T cell subsets or neutralized the inflammatory cytokines IFN-γ, IL-12, or TNF in TNFRp55−/− mice infected i.v. with M. avium. Infected TNFRp55−/− mice treated with a control mAb became moribund between days 26 and 34 postinfection, showing widespread inflammatory cell apoptosis within disintegrating granulomas. In contrast, TNFRp55−/− mice depleted of either CD4+ or CD8+ cells after granuloma initiation stayed healthy until at least day 38 postinfection and showed no signs of granuloma destruction. Neutralization of IL-12, but not of IFN-γ or TNF, also protected M. avium-infected TNFRp55−/− mice from granuloma decomposition and from premature death. Treatment with dexamethasone or with a specific inhibitor of inducible NO synthase did not prevent granuloma dissolution or death of TNFRp55−/− mice. In conclusion, granuloma disintegration in TNFRp55−/− mice is a lethal event that is dependent on IL-12 and that is mediated by an excess of T cells.

Virulent Toxoplasma gondii strain RH promotes T-cell-independent overproduction of proinflammatory cytokines IL12 and γ-interferon

“…These differences might be due to the genetic background of the animals, since they used CD1 mice, when we infected BALB/c mice. Similarly, Ehlers et al (2000) reported that the TNFRp55-deficient mice succumb to infection with Mycobacterium avium due to high levels of IL12, with necrotic foci in the livers. Gram-negative bacterial septicaemia, with accompanying endogenous endotoxinaemia induces high levels of IL12, IFN-ª and TNF-AE production, contributing much to the pathological findings and lethality observed in experimental toxic shock (Heinzel et al, 1994;Ozmen et al, 1994;Wysocka et al, 1995).…”

“…For example, cerebral malaria is thought to be mediated by parasite-induced TNF-AE (Grau et al, 1987). More recently, it has been shown that TNFRp55-deficient mice die after infection with Mycobacterium avium due to high levels of IL12 (Ehlers et al, 2000).…”

The Lymphotoxin β Receptor Is Critically Involved in Controlling Infections with the Intracellular Pathogens Mycobacterium tuberculosis and Listeria monocytogenes

“…In particular, TNFRp55-KO mice succumbed to challenges with L. monocytogenes, Mycobacterium avium, or M. tuberculosis, showing unaltered or only slightly delayed recruitment of inflammatory cells into infectious lesions (26,27,29). To dissect the ligands involved, studies were also performed in TNF-KO mice and in LT␣-KO mice (31,44).…”

“…In combination with the membranebound LT␤, LT␣ binds as the LT␣ 1 ␤ 2 heterotrimer to the LT␤R (16,21,23,24). TNF 3 , LT␣ 3 in concert with the TNFRp55, were shown to be of critical importance for the host defense against intracellularly replicating bacterial pathogens and for the formation and maintenance of fully differentiated granulomas (25)(26)(27)(28)(29)(30)(31). In contrast, the detailed role of the LT␤R and its cognate ligands in antimicrobial resistance and granuloma formation has remained unexplored.…”

Execution of Macrophage Apoptosis by PE_PGRS33 of Mycobacterium tuberculosis Is Mediated by Toll-like Receptor 2-dependent Release of Tumor Necrosis Factor-α

“…It is widely accepted that TNF-␣ 5 is essential for the maintenance of the granuloma and the control of tuberculosis (2). Hosts with a deficiency in TNF-␣ or its receptors are susceptible to mycobacterial infection (3)(4)(5)(6)(7)(8). TNF-␣ controls both the innate and the adaptive arms of the immune response against tuberculosis.…”