IL‐18 and infections: Is there a role for targeted therapies?

Abstract Interleukin (IL)‐18 is a pro‐inflammatory cytokine belonging to the IL‐1 family, first identified for its interferon‐γ‐inducing properties. IL‐18 regulates both T helper (Th) 1 and Th2 responses. It acts synergistically with IL‐12 in the Th1 paradigm, whereas with IL‐2 and without IL‐12 it can induce Th2 cytokine production from cluster of differentation (CD)4 + T cells, natural killer (NK cells, NKT cells, as well as from Th1 cells. IL‐18 also plays a role in the hemophagocytic lymphohistiocytosis, a life‐threatening condition characterized by a cytokine storm that can be secondary to infections. IL‐18‐mediated inflammation was largely studied in animal models of bacterial, viral, parasitic, and fungal infections. These studies highlight the contribution of either IL‐18 overproduction by the host or overresponsiveness of the host to IL‐18 causing an exaggerated inflammatory burden and leading to tissue injury. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is responsible for the coronavirus disease 2019 (COVID‐19). The damage in the later phase of the disease appears to be driven by a cytokine storm, including interleukin IL‐1 family members and secondary cytokines like IL‐6. IL‐18 may participate in this hyperinflammation, as it was previously found to be able to cause injury in the lung tissue of infected animals. IL‐18 blockade has become an appealing therapeutic target and has been tested in some IL‐18‐mediated rheumatic diseases and infantile‐onset macrophage activation syndrome. Given its role in regulating the immune response to infections, IL‐18 blockade might represent a therapeutic option for COVID‐19, although further studies are warranted to investigate more in detail the exact role of IL‐18 in SARS‐CoV‐2 infection.