Abstract
Macrophages are the first line of defense against pathogens. Upon infection macrophages usually produce high levels of proinflammatory mediators. However, macrophages can undergo an alternate polarization leading to a permissive state. In assessing global macrophage responses to the bacterial agent of Whipple's disease, Tropheryma whipplei, we found that T. whipplei induced M2 macrophage polarization which was compatible with bacterial replication. Surprisingly, this M2 polarization of infected macrophages was associated with apoptosis induction and a functional type I interferon (IFN) response, through IRF3 activation and STAT1 phosphorylation. Using macrophages from mice deficient for the type I IFN receptor, we found that this type I IFN response was required for T. whipplei-induced macrophage apoptosis in a JNK-dependent manner and was associated with the intracellular replication of T. whipplei independently of JNK. This study underscores the role of macrophage polarization in host responses and highlights the detrimental role of type I IFN during T. whipplei infection.
Highlights
Over the past decades, activated macrophages were mainly considered as cells that secrete inflammatory mediators and kill intracellular pathogens
We have shown that T. whipplei induces host cell apoptosis and a surprising macrophage activation, characterized by anti-inflammatory molecules and type I interferon (IFN) signaling, which is generally associated to viral infections
We demonstrate that this type I IFN response is critical for bacterial pathogenicity, as it is required for bacterial replication and provides the first step of the apoptotic program of infected macrophages
Summary
Over the past decades, activated macrophages were mainly considered as cells that secrete inflammatory mediators and kill intracellular pathogens. Studies have revealed activated macrophages as a continuum of cells with phenotypic and functional heterogeneity [1,2]. Macrophages exposed to the classic activation signals (lipopolysaccharide (LPS) and/or IFN-c) polarize into the M1 phenotype and express high levels of TNF, IL-1, IL-6, IL-12, type I IFN, inflammatory chemokines, such as CXCL10, and inducible nitric oxide synthase. M2 macrophages, induced by IL-4, IL-10 or immune complexes, are characterized by the expression of non-opsonic receptors, arginase, and the absence of proinflammatory cytokines [3,4]. Successful infection by pathogenic intracellular bacteria usually relies on the perturbation or avoidance of the classical M1 proinflammatory activation profile [3]
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