Signaling via the IL-20 receptor inhibits cutaneous production of IL-1β and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus

Abstract

Staphylococcus aureus causes the majority of human skin and soft tissue infections, and is a major infectious cause of mortality. Host defense mechanisms against S. aureus are incompletely understood. Interleukin (IL)-19, -20 and -24 signal through type I and type II IL-20 receptors and are associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We show here that these cytokines promote cutaneous S. aureus infection in mice by downregulating IL-1β- and IL-17A-dependent pathways. Similar effects of these cytokines were seen in human keratinocytes after S. aureus exposure, and antibody blockade of IL-20 receptor improved outcomes in infected mice. Our findings identify an immunosuppressive role for these cytokines during infection that could be therapeutically targeted to alter susceptibility to infection.

Immunomodulatory effects of pCramoll and rCramoll on peritoneal exudate cells (PECs) infected and non-infected with Staphylococcus aureus

“…These results corroborate the previous study by Zhao and co-workers [33], demonstrating that IFN-␥ regulates the levels of proinflammatory cytokines during S. aureus infection. Although IL-1␤ and IFN-␥ are proinflammatory cytokines, their suppression by S. aureus has been described as a mechanism for evading the host defense response [33][34][35]. Although the molecular mechanism underlying the suppression of IL-6 and TNF-␣ induced by lectin treatment in PECs infected with S. aureus remains to be elucidated, it is possible that decreases in these cytokines help to attenuate the deleterious effects of persistent inflammatory responses at the site of infection.…”

The IL-20 subfamily of cytokines — from host defence to tissue homeostasis

“…Resistance to primary infection with S. aureus crucially depends on the early production of IL-1β and IL-17 by skin-resident cells, and the downstream recruitment of neutrophils 99,100 . A recent report shows how IL-19, IL-20 and IL-24 are induced locally by S. aureus, and how these cytokines potently inhibit the generation of IL-1β and IL-17, eventually resulting in a greater severity of infection 98 . In IL-20RB-deficient mice, intradermal injection of S. aureus resulted in smaller lesions and a lower bacterial burden compared with wild-type mice, whereas co-injection of S. aureus with recombinant IL-19 or IL-20 led to more severe infection and reduced neutrophil recruitment 98 .…”

“…One such example is Staphylococcus aureus, which infects the skin 98 . Resistance to primary infection with S. aureus crucially depends on the early production of IL-1β and IL-17 by skin-resident cells, and the downstream recruitment of neutrophils 99,100 .…”

Interleukin-10 Superfamily and Cancer

“…In addition, it was also found that proinflammatory IL-1β is able to upregulate IL-20 through stress-activated kinase 1 (MSK1) NF-κB-and MAPK-dependent mechanisms (Otkjaer et al, 2007). Interestingly, other investigators demonstrated that IL-20 downregulated IL-1β and IL-17A, thereby promoting infection in mice (Myles et al, 2013). Finally, IL-20 was associated with Jak/STAT3 expression and signaling in nonlesional psoriatic skin (Andrés et al, 2013).…”