Abstract
Propionibacterium acnes is usually a relatively harmless commensal. However, under certain, poorly understood conditions it is implicated in the etiology of specific inflammatory diseases. In mice, P. acnes exhibits strong immunomodulatory activity leading to splenomegaly, intrahepatic granuloma formation, hypersensitivity to TLR ligands and endogenous cytokines, and enhanced resistance to infection. All these activities reach a maximum one week after P. acnes priming and require IFN-γ and TLR9. We report here the existence of a markedly delayed (1–2 weeks), but phenotypically similar TLR9-independent immunomodulatory response to P. acnes. This alternative immunomodulation is also IFN-γ dependent and requires functional MyD88. From our experiments, a role for MyD88 in the IFN-γ-mediated P. acnes effects seems unlikely and the participation of the known MyD88-dependent receptors, including TLR5, Unc93B-dependent TLRs, IL-1R and IL-18R in the development of the alternative response has been excluded. However, the crucial role of MyD88 can partly be attributed to TLR2 and TLR4 involvement. Either of these two TLRs, activated by bacteria and/or endogenously generated ligands, can fulfill the required function. Our findings hint at an innate immune sensitizing mechanism, which is potentially operative in both infectious and sterile inflammatory disorders.
Highlights
IntroductionThe Gram-positive bacterium Propionibacterium acnes (formerly C. parvum) is a part of the human and mouse flora and an opportunistic human pathogen
The Gram-positive bacterium Propionibacterium acnes is a part of the human and mouse flora and an opportunistic human pathogen
We showed previously that the absence of TLR9 impairs the development of immunomodulatory effects by P. acnes [9]
Summary
The Gram-positive bacterium Propionibacterium acnes (formerly C. parvum) is a part of the human and mouse flora and an opportunistic human pathogen. It has been implicated as an etiologic agent of specific inflammatory diseases, including sarcoidosis [1,2,3]. Infection with live or administration of heatkilled P. acnes in experimental animals and humans leads to a strong activation of the reticulo-endothelial system. P. acnes induces several immunomodulatory activities, including intra-hepatic granuloma formation, splenomegaly, enhanced resistance to infection and malignant tumors as well as hypersensitivity to microbial Toll-like receptor (TLR) agonists, such as lipopolysaccharide (LPS), lipopeptides (LP) or synthetic CpG DNA analogs [4]. P. acnes-primed mice develop hypersensitivity to the endogenous mediators TNF-a and IL-12 [4,5,6]
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