The Role of IL-23 in Regulating the Recruitment and Function of Phagocytic Cells during Listeria monocytogenes infection

The IL-23/IL-17 axis is detrimental during autoimmune disorders, but is protective against certain pathogens, particularly extracellular bacteria. We have previously shown that IL-23 is required for host resistance against Listeria monocytogenes (LM) and for neutrophil recruitment to the liver, but not the spleen, during infection. Despite efficient neutrophil recruitment to the spleen, IL-23p19 knockout (KO) mice have an increased bacterial burden in this organ compared to C57BL/6 (B6) mice. Interestingly, specific depletion of neutrophils abrogated the differences in bacterial burden in the liver, but not the spleen of B6 and IL-23p19 KO mice, suggesting that IL-23 may regulate the recruitment/function of another cell type in the spleen. Accordingly, LM-infected IL- 23p19 KO mice had fewer inflammatory monocytes in the spleen as well as a reduction in monocyte-recruiting chemokines compared to B6 mice. Therefore, IL-23 is necessary for the optimal recruitment of inflammatory monocytes to the spleen during LM infection. Phagocytic cells express receptors for IL-23 and IL-17A suggesting that the activity of these cells could be regulated by IL-23 or IL-17A. However, it is not known whether IL-23 could impact the function of phagocytic cells during LM infection. Inflammatory monocytes, neutrophils, and macrophages from B6 and IL-23p19 KO mice displayed equivalent phagocytic potential. Although exogenous stimulation with IL-23 and IL-6 increased the production of ROS from B6 neutrophils, the absence of IL-23 did not impact the ability of inflammatory monocytes and neutrophils to make ROS during LM infection. Additionally, the expression of myeloperoxidase (MPO), inducible nitric oxide (iNOS), and TNF-α by inflammatory monocytes, neutrophils, and peritoneal macrophages was not altered by the lack of IL-23 during LM infection. Therefore, IL-23 is not required for the optimal function of phagocytic cells during LM infection. The proinflammatory mediators, TNF-α and NO, are essential for protection against LM. Surprisingly, there was a reduction in the overall levels of TNF-α and NO in the spleen of IL-23p19 KO mice compared to B6 mice during LM infection. However, exogenous stimulation with IL-23 or IL-17A did not induce or enhance the production of these proinflammatory mediators from splenocytes isolated from LM-infected B6 mice. Interestingly, the reduction in overall production of TNF-α and NO. in the spleens of LMinfected IL-23p19 KO mice, corresponds with reduced numbers and percentages of TNF- α and iNOS-expressing monocytes. This deficient recruitment of inflammatory monocytes resulted in decreased production of monocyte-derived TNF-α and NO, leading to increased bacterial burdens in the spleens of LM-infected IL-23p19 KO mice. Collectively, our data reveal that the enhanced susceptibility of IL-23p19 KO mice is not due to functional impairment of phagocytic cells, instead it is caused by the inefficient recruitment of neutrophils to the liver, and inflammatory monocytes to the spleen, during LM infection.