Abstract
Signal transducer and activator of transcription 4 (STAT4) is expressed in hematopoietic cells and plays a key role in the differentiation of T helper 1 cells. Although STAT4 is required for immunity to intracellular pathogens, the T cell–independent protective mechanisms of STAT4 are not clearly defined. In this report, we demonstrate that STAT4-deficient mice were acutely sensitive to methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that STAT4 was expressed in neutrophils and activated by IL-12 via a JAK2-dependent pathway. We demonstrate that STAT4 was required for multiple neutrophil functions, including IL-12–induced ROS production, chemotaxis, and production of the neutrophil extracellular traps. Importantly, myeloid-specific and neutrophil-specific deletion of STAT4 resulted in enhanced susceptibility to MRSA, demonstrating the key role of STAT4 in the in vivo function of these cells. Thus, these studies identify STAT4 as an essential regulator of neutrophil functions and a component of innate immune responses in vivo.
Highlights
Signal transducer and activator of transcription (STAT) proteins are a family of factors implicated in various biological processes, including the induction of genes involved in cell differentiation [1]
Much of the research on IL-12– and IFN-α–dependent functions of Signal transducer and activator of transcription 4 (STAT4) has been performed in T and NK cells [8]; evidence suggests that STAT4 is expressed in activated monocytes, macrophages, and dendritic cells
We demonstrated that JAK2, an upstream signaling kinase of STAT4, underwent rapid phosphorylation upon IL-12 stimulation (Figure 1B)
Summary
Signal transducer and activator of transcription (STAT) proteins are a family of factors implicated in various biological processes, including the induction of genes involved in cell differentiation [1]. STAT4 is required for all known IL-12 biological functions, including the induction of IFN-γ and the promotion of T helper type 1 (Th1) differentiation [5, 6]. In models of infection and autoimmunity, STAT4 is a critical component in developing inflammation [8]. STAT4-deficient mice are susceptible to infection with intracellular pathogens, have decreased delayed-type hypersensitivity (DTH) responses [8], and have attenuated T cell responses [5, 6]. STAT4-deficient mice are refractory to the induction of inflammatory conditions, including colitis, arthritis, diabetes, myocarditis, and experimental autoimmune encephalitis [7].
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