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Macrophages are important innate immune defense system cells in the fight against bacterial and fungal pathogenic infections. They exhibit significant plasticity, particularly with their ability to undergo functional differentiation. Additionally, HIF1α is critically involved in the functional differentiation of macrophages during inflammation. However, the role of macrophage HIF1α in protecting against different pathogenic infections remains unclear. In this study, we investigated and compared the roles of HIF1α in different macrophage functional effects of bacterial and fungal infections in vitro and in vivo. We found that bacterial and fungal infections produced similar effects on macrophage functional differentiation. HIF1α deficiency inhibited pro-inflammatory macrophage functional activities when cells were stimulated with LPS or curdlan in vitro or when mice were infected with L. monocytogenes or C. albicans in vivo, thus decreasing pro-inflammatory TNFα and IL-6 secretion associated with pathogenic microorganism survival. Alteration of glycolytic pathway activation was required for the functional differentiation of pro-inflammatory macrophages in protecting against bacterial and fungal infections. Thus, the HIF1α-dependent glycolytic pathway is essential for pro-inflammatory macrophage functional differentiation in protecting against bacterial and fungal infections.

The protein Tir (translocated intimin receptor) in enteric bacteria shares sequence similarity with the host cellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). Despite the importance of Tir in pedestal formation, relatively little is known about the role of Tir and its ITIMs in the regulation of the host immune response. Here we demonstrate that Tir from enteropathogenic Escherichia coli (EPEC) interacted with the host cellular tyrosine phosphatase SHP-1 in an ITIM phosphorylation-dependent manner. The association of Tir with SHP-1 facilitated the recruitment of SHP-1 to the adaptor TRAF6 and inhibited the ubiquitination of TRAF6. Moreover, the ITIMs of Tir suppressed EPEC-stimulated expression of proinflammatory cytokines and inhibited intestinal immunity to infection with Citrobacter rodentium. Our findings identify a previously unknown mechanism by which bacterial ITIM-containing proteins can inhibit innate immune responses.

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