IL-4 subverts protective immunity to multiple intracellular pathogens including the fungus Histoplasma capsulatum. Previously, we reported that H. capsulatum-challenged CCR2−/− mice manifest elevated pulmonary fungal burden due to exaggerated IL-4. Paradoxical to our anticipation in IL-33 driving IL-4, we discovered the latter prompted IL-33 in mutant mice. In infected CCR2−/− animals, amplified IL-33 succeeded the heightened IL-4 response and inhibition of IL-4 signaling decreased IL-33. Moreover, macrophages, but not epithelial cells or dendritic cells from these mice expressed higher IL-33 in comparison to controls. Dissection of mechanisms that promulgated IL-33 revealed type-II cytokines and H. capsulatum synergistically elicited an IL-33 response in macrophages via STAT6/IRF-4 and Dectin-1 pathways respectively. Neutralizing IL-33 in CCR2−/− animals, but not controls, enhanced their resistance to histoplasmosis. Thus, we describe a previously unrecognized role for IL-4 in instigating IL-33 in macrophages. Furthermore, in presence of intracellular fungal pathogens, the type-II cytokine-driven IL-33 response impairs immunity.

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide, and interleukin-22 (IL-22) helps contain pneumococcal burden in lungs and extrapulmonary tissues. Administration of IL-22 increases hepatic complement 3 and complement deposition on bacteria and improves phagocytosis by neutrophils. The effects of IL-22 can be tempered by a secreted natural antagonist, known as IL-22 binding protein (IL-22BP), encoded by Il22ra2. To date, the degree to which IL-22BP controls IL-22 in pulmonary infection is not well defined. Here, we show that Il22ra2 inhibits IL-22 during S. pneumoniae lung infection and that Il22ra2 deficiency favors downregulation of oxidative phosphorylation (OXPHOS) genes in an IL-22-dependent manner. Il22ra2−/− mice are more resistant to S. pneumoniae infection, have increased IL-22 in lung tissues, and sustain longer survival upon infection than control mice. Transcriptome sequencing (RNA-seq) analysis of infected Il22ra2−/− mouse lungs revealed downregulation of genes involved in OXPHOS. Downregulation of this metabolic process is necessary for increased glycolysis, a crucial step for transitioning to a proinflammatory phenotype, in particular macrophages and dendritic cells (DCs). Accordingly, we saw that macrophages from Il22ra2−/− mice displayed reduced OXPHOS gene expression upon infection with S. pneumoniae, changes that were IL-22 dependent. Furthermore, we showed that macrophages express IL-22 receptor subunit alpha-1 (IL-22Ra1) during pneumococcal infection and that Il22ra2−/− macrophages rely more on the glycolytic pathway than wild-type (WT) controls. Together, these data indicate that IL-22BP deficiency enhances IL-22 signaling in the lung, thus contributing to resistance to pneumococcal pneumonia by downregulating OXPHOS genes and increasing glycolysis in macrophages.

Tumor necrosis factor (TNF) antagonists are popular therapies for inflammatory diseases. These agents enhance the numbers and function of regulatory T cells (Tregs), which are important in controlling inflammatory diseases. However, elevated Treg levels increase susceptibility to infections, including histoplasmosis. We determined the mechanism by which Tregs expand in TNF-neutralized mice infected with Lung CD11c CD11b dendritic cells (DCs), but not alveolar macrophages, from -infected mice treated with anti-TNF induced a higher percentage of Tregs than control DCs CD11b CD103 DCs, understood to be unique to the intestines, were augmented in lungs with anti-TNF treatment. In the absence of this subset, DCs from anti-TNF-treated mice failed to amplify Tregs CD11b CD103 DCs from TNF-neutralized mice displayed higher retinaldehyde dehydrogenase 2 (RALDH2) gene expression, and CD11b CD103 RALDH DCs exhibited greater enzyme activity. To determine if CD11b CD103 DCs migrated from gut to lung, fluorescent beads were delivered to the gut via oral gavage, and the lungs were assessed for bead-containing DCs. Anti-TNF induced migration of CD11b CD103 DCs from the gut to the lung that enhanced the generation of Tregs in -infected mice. Therefore, TNF neutralization promotes susceptibility to pulmonary infection by promoting a gut/lung migration of DCs that enhances Tregs.

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