From the AGA Journals

IL-23 plays key roles in antimicrobial macrophage activity

View on the News

Does blocking IL-23 in IBD predispose to infections?

Both genetic studies in humans and functional studies in mice have pinpointed interleukin-23 and its receptor as a key pathway in the pathogenesis of inflammatory bowel disease (IBD). IL-23 is released from myeloid cells in response to sensing of invading pathogens or danger-associated molecular patterns, where it drives induction of Th17, innate lymphoid cell responses, and inflammation.

Dr. Alison Simmons is a professor in gastroenterology, University of Oxford and Translational Gastroenterology Unit, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

Dr. Alison Simmons

Sun and Abraham describe a new function for IL-23 acting in a paracrine manner on macrophages to accelerate uptake and destruction of incoming bacteria via reactive oxygen, reactive nitrogen, and autophagic routes. The authors then explore how expression of IBD-protective IL23 receptor susceptibility variants located in the IL-23R cytoplasmic tail might affect this pathway. They find the IBD-protective IL-23R–R381Q variant reduces uptake and degradation of bacteria, in addition to its role in reducing amplitude of inflammatory responses. Whether possession of the common IL-23R–R381Q variant predisposes to adverse sequelae during infections or whether blocking IL-23 in IBD may predispose to specific infections remains to be seen. In which case, it will be important to further dissect the mechanism of IL-23R signaling to ensure therapies selectively target inflammatory drivers while retaining protective effects.

Alison Simmons, FRCP, PhD, is professor of gastroenterology, honorary consultant gastroenterologist, MRC human immunology unit, Weatherall Institute of Molecular Medicine, University of Oxford (England), and translational gastroenterology unit, Oxford University Hospitals NHS Trust. She has consultancies from AbbVie, Bristol-Myers Squibb, and Janssen, and is a cofounder and equity holder in TRexBio.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

Interleukin-23 optimizes antimicrobial macrophage activity, which is reduced among persons harboring an IL-23 receptor variant that helps protect against inflammatory bowel disease (IBD), recent research has found.

“These [findings] highlight that the susceptibility to infections with therapeutic blockade of the IL-23/IL-12 pathways may be owing in part to the essential role for IL-23 in mediating antimicrobial functions in macrophages. They further highlight that carriers of the IL-23R–Q381 variant, who are relatively protected from IBD and other immune-mediated diseases, may be at increased risk for bacterial infection,” Rui Sun and Clara Abraham, MD, of Yale University, New Haven, Conn., wrote in Cellular and Molecular Gastroenterology and Hepatology.

IL-23 is key to the pathogenesis of IBD and is being studied as a therapeutic target, both alone and in combination with IL-12 blocking. Although human macrophages express low levels of IL-23 receptor, recent research reveals that IL-23R is up-regulated “within minutes of exposure to IL-23,” which promotes signaling and cytokine secretion, the investigators wrote. However, the extent to which IL-23 supports macrophage antimicrobial activity was unknown. To characterize protein expression, signaling, and bacterial uptake and clearance of bacteria by human macrophages derived from monocytes, the investigators tested these cells with Western blot, flow cytometry, and gentamicin protection, which involved coculturing human macrophages with bacteria, adding gentamicin solution, and then lysing and plating the cells onto agar to assess the extent to which the macrophages had taken up the bacteria.

After 48 hours of exposure to IL-23 or IL-12, macrophages increased their intracellular clearance of clinically relevant bacteria, including Enterococcus faecalis, adherent invasive Escherichia coli, and Salmonella typhimurium. Notably, this did not occur when the investigators reduced (“knocked down”) macrophage expression of either IL-23R or IL-12 receptor alpha 2. Additional investigations showed that in macrophages, IL-23 promotes bacterial uptake, clearance, and autophagy by inducing a pyruvate dehydrogenase kinase 1 (PDK1)–dependent pathway mediated by Janus kinase 2/tyrosine kinase 2 and by inducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) pathways. IL-23 also activates two key proteins involved in autophagy (ATG5 and ATG16L1), the researchers reported. “ROS, RNS, and autophagy cooperate to mediate IL-23-induced bacterial clearance. Reduction of each ROS, RNS, and autophagy pathway partially reversed the enhanced bacterial clearance observed with chronic IL-23 treatment.”

Further tests found that IL-23 mediates antimicrobial pathways through the Janus kinase 2, tyrosine kinase 2, and STAT3 pathways, which “cooperate to mediate optimal IL-23-induced intracellular bacterial clearance in human macrophages.” Importantly, human macrophages showed less antimicrobial activity when transfected with the IL-23R–Q381 variant than with IL-23R–R381. The IL-23R-Q381 variant, which reduces susceptibility to IBD, “decreased IL-23-induced and NOD2-induced antimicrobial pathways and intracellular bacterial clearance in monocyte-derived macrophages,” the researchers explained. Evaluating actual carriers of these variants showed the same results – macrophages harboring IBD-protective IL-23R–R381/Q381 exhibited lower antimicrobial activity and less intracellular bacterial clearance compared with macrophages from carriers of IL-23R–R381/R381.

“Taken together, IL-23 promotes increased bacterial uptake and then induces a more rapid and effective clearance of these intracellular bacteria in human monocyte-derived macrophages,” the researchers wrote. “The reduced inflammatory responses observed in IL-23R Q381 carriers are associated with protection from multiple immune-mediated diseases. This would imply that loss-of-function observed with the common IL-23R–R381Q variant may lead to a disadvantage in select infectious diseases, including through [this variant’s] now identified role in promoting antimicrobial pathways in macrophages.”

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.

SOURCE: Sun R, Abraham C. Cell Molec Gastro Hepatol. 2020 May 28. doi.: 10.1016/j.jcmgh.2020.05.007.

Next Article: