Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

Abstract

Tumor necrosis factor (TNF) plays a critical role in the host response to the intracellular pathogen Listeria monocytogenes (LM). TNF exists in soluble and membrane-bound forms and exhibits both unique and overlapping activities. We examined the role of membrane TNF in the absence of secreted TNF for host resistance in knockin mice in which the endogenous TNF was replaced by a regulated, noncleavable allele (mem-TNF). Macrophages expressing mem-TNF produced nitric oxide and displayed normal bactericidal activity. Although mice completely deficient in TNF (TNF ؊/؊ ) succumbed to LM infection within 4 days, mem-TNF mice controlled LM infection at a low dose (10 4 CFU) but succumbed at a higher dose of infection (10 5 CFU). In contrast to complete TNF deficiency, mem-TNF mice developed confined microabscesses that expressed inducible nitric oxide synthase. The transfer of lymphocytes from immunized mem-TNF, but not TNF ؊/؊ , mice protected TNF ؊/؊ mice from fatal infection. Taken Protective immunity to Listeria monocytogenes (LM) infection, both in humans and experimental animals, is based on orchestrated action of T cells, macrophages, and cytokines, including interferon (IFN)-␥, interleukin (IL)-12, and tumor necrosis factor (TNF). 1 A critical role for TNF in anti-LM defense is inferred from neutralization and gene deletion experiments in mice. 2,3 In addition, the TNFrelated cytokines lymphotoxin (LT)-␣ and LT-␤ are also required to control LM infection. 4 Both secreted TNF and LT-␣ signal through p55 and p75 TNF receptors (TNFR1 and TNFR2, respectively). The cell-bound LT-␣␤ heterotrimers recognize the LT-␤R. TNF-R1 signaling appears to be critical for the control of LM infection 2,3 and LT-␤R also plays a distinct role, while the contribution of TNFR2 is less well defined.TNF is expressed by a variety of cells, including macrophages and T cells, and is a major regulator of inflammation and leukocyte trafficking. 5 TNF is first produced as an integral membrane protein and is subsequently cleaved by the metalloproteinase-disintegrin TACE (TNF-␣ converting enzyme) 6,7 into the secreted trimeric TNF. Although the role of TNF in controlling intracellular bacterial infections is uncontested, the function of membrane TNF in host resistance is less understood.Several biological functions of membrane TNF have been described, such as cytotoxicity, polyclonal activation of B cells, induction of IL-10 by monocytes, induction of chemokines, and ICAM-1 expression on endothelial cells. 8 -10 The transgenic overexpression of membrane TNF has demonstrated an in vivo role in the control of LM and mycobacterial infection. [11][12][13] However, these models were potentially nonphysiological as transgenic expression of a membrane-only form of TNF results in artificially high and nonselective expression of membrane TNF. The recent generation of mice with functional, normally regulated and expressed membrane-bound TNF, obtained by knocking-in an uncleavable ⌬1-9, K11E TNF allele (mem-TNF mice), represents a major advance and allo...

A Virus-Like Particle-Based Vaccine Selectively Targeting Soluble TNF-α Protects from Arthritis without Inducing Reactivation of Latent Tuberculosis

“…These latter mice can still form compact granulomas, which prevent bacterial spreading, whereas mice completely lacking TNF-␣ are severely impaired in granuloma formation. Expression of a functional transmembrane form of TNF-␣ also confers partial protection to L. monocytogenes infection (28,29), whereas TNF-␣-or TNF-RIdeficient mice are highly susceptible (16, 29 -31).…”

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

“…The mTNF Á/Á mice were generated by replacing the endogenous TNF allele with the Á1-9, K11E TNF allele. This combined deletion/mutation guarantees loss of TACE-mediated cleavage preventing shedding of solTNF, 19,43 but maintains normal cell-surface expression and function of mTNF. 19 We show that transgenic mTNF Á/Á mice have no abnormal behavioral or histopathological phenotypes when compared to mTNF wt/wt wild-type (WT) littermates.…”

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

“…A recent report using memTNF D1-9,K11E mutant mice indicated that tmTNF is sufficient to provide acute but not longterm control of Mycobacterium tuberculosis infection [44]. The same mutant strain of mice was also reported to be partially protected from LM infection [58]. Interestingly, in the present study, despite the reported partial deficiency of the tmTNF D1-12 mutant in activation of the p55TNFR in cellular assays (as described in [36]), mutant Tnf tm/tm mice also appear to be significantly protected from LM infections, especially following more physiological doses of bacteria (e.g.…”