STAT3 mediates an inflammation-induced microbial defense response and regulates pathogen control and clearance by macrophages

STAT3 is pivotal for governing myeloid responses to inflammatory stimuli to prevent hyperinflammation in vivo, yet whether STAT3 mediates pathogen control and clearance by myeloid cells remains unclear. In this study, we identified significant enrichment of IFN-stimulated transcriptional pathways in Stat3-deficient bone marrow-derived macrophages (BMDMs) at steady state. This was accompanied by activation of autocrine type I IFN (IFN-I) and aberrant autocrine IL-6 signaling associated with increased STAT1 activity. Despite exaggerated baseline IFN-STAT1 signaling, Stat3-deficient BMDMs were significantly impaired in their ability to induce expression of key pathogen defense genes and specific immune mediators upon LPS stimulation. STAT3 was also required in Citrobacter rodentium-infected BMDMs for expression of pathogen defense genes and effective bacterial killing. Moreover, bone marrow chimeric mice with 20% Stat3-deficient hematopoietic cells were more susceptible to infection with C. rodentium and showed increased bacterial dissemination and reduced production of specific cytokines. IL-6 blockade subdued the intrinsic IFN response and rescued expression of select pathogen defense genes in Stat3-deficient BMDMs upon LPS stimulation yet was unable to restore bacterial killing activity. Taken together, our results identify novel functions for STAT3 in orchestrating an optimal microbial defense response and suggest this is regulated by discrete mechanisms including modulation of autocrine IL-6 signaling in macrophages.