BATF2 enhances proinflammatory cytokine responses in macrophages and improves early host defense against pulmonary infection.

Basic leucine zipper transcription factor ATF-like 2 (BATF2) is a transcription factor that is emerging as an important regulator of the innate immune system. BATF2 is among the top upregulated genes in human alveolar macrophages treated with LPS, but the signaling pathways that induce BATF2 expression in response to Gram-negative stimuli are incompletely understood. In addition, the role of BATF2 in the host response to pulmonary infection with a Gram-negative pathogen like () is not known. We show that induction of gene expression in macrophages in response to in vitro requires TRIF and type I interferon (IFN) signaling, but not MyD88 signaling. Analysis of the impact of BATF2 deficiency on macrophage effector functions in vitro showed that BATF2 does not directly impact macrophage phagocytic uptake and intracellular killing of . However, BATF2 markedly enhanced macrophage proinflammatory gene expression and -induced cytokine responses. In vivo, gene expression was elevated in lung tissue of wild-type (WT) mice 24 h after pulmonary infection, and -infected BATF2-deficient () mice displayed an increase in bacterial burden in the lung, spleen, and liver compared with WT mice. WT and mice showed similar recruitment of leukocytes following infection, but in line with in vitro observations, proinflammatory cytokine levels in the alveolar space were reduced in mice. Altogether, these results suggest that BATF2 enhances proinflammatory cytokine responses in macrophages in response to and contributes to the early host defense against pulmonary infection. This study investigates the signaling pathways that mediate induction of BATF2 expression downstream of TLR4 and also the impact of BATF2 on the host defense against pulmonary infection. We demonstrate that -induced upregulation of BATF2 in macrophages requires TRIF and type I IFN signaling. We also show that BATF2 enhances -induced macrophage cytokine responses and that BATF2 contributes to the early host defense against pulmonary infection.