IL-27 Induced by SelectCandidaspp. via TLR7/NOD2 Signaling and IFN-β Production Inhibits Fungal Clearance

Abstract

Candida spp. elicit cytokine production downstream of various pathogen recognition receptors, including C-type lectin-like receptors, TLRs, and nucleotide oligomerization domain (NOD)–like receptors. IL-12 family members IL-12p70 and IL-23 are important for host immunity against Candida spp. In this article, we show that IL-27, another IL-12 family member, is produced by myeloid cells in response to selected Candida spp. We demonstrate a novel mechanism for Candida parapsilosis–mediated induction of IL-27 in a TLR7-, MyD88-, and NOD2-dependent manner. Our data revealed that IFN-β is induced by C. parapsilosis, which in turn signals through the IFN-α/β receptor and STAT1/2 to induce IL-27. Moreover, IL-27R (WSX-1)–deficient mice systemically infected with C. parapsilosis displayed enhanced pathogen clearance compared with wild-type mice. This was associated with increased levels of proinflammatory cytokines in the serum and increased IFN-γ and IL-17 responses in the spleens of IL-27R–deficient mice. Thus, our data define a novel link between C. parapsilosis, TLR7, NOD2, IFN-β, and IL-27, and we have identified an important role for IL-27 in the immune response against C. parapsilosis. Overall, these findings demonstrate an important mechanism for the suppression of protective immune responses during infection with C. parapsilosis, which has potential relevance for infections with other fungal pathogens.

IL-27: a double agent in the IL-6 family

“…properties of type I IFNs are attributed largely to the upregulation of IL-27 and the subsequent promotion of IL-10 [19][20][21]. Consistent with these observations, prominent immunosuppressive roles were discovered for IL-27 through investigations in mouse models of chronic infection and autoimmunity [22][23][24][25][26].…”

“…For example, IL‐27 is required for the development of T‐bet + and C‐X‐C motif chemokine receptor 3 (CXCR3) + regulatory T cell (T reg ) populations following T helper type 1 (Th1)‐mediated inflammation using Toxoplasma gondii ‐challenged IL‐27R‐deficient mice . In this regard, the anti‐inflammatory properties of type I IFNs are attributed largely to the up‐regulation of IL‐27 and the subsequent promotion of IL‐10 . Consistent with these observations, prominent immunosuppressive roles were discovered for IL‐27 through investigations in mouse models of chronic infection and autoimmunity .…”

Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence

“…Direct ex vivo intracellular IL-27 production was detected as previously described [71]. Cells were stained with a combination of anti-I-A/I-E (clone M5/114.15.2, Biolegend), anti-CD11c Pe-Cy7 (clone HL3 BD, Pharmingen), anti-Ly6C FITC (clone AL-21 BD Pharmingen), anti-CD11b APC-Cy7 (clone M1/70, Biolegend), anti-F480 Brilliant-Violet 711 (BV711) (clone BM8, Biolegend), anti-CD45R/B220 BV785 (clone RA3-6B2, Biolegend), SiglecH APC (clone 551, Biolegend), anti-Ly6G PerCP-Cy5.5 (clone 1A8, Biolegend), and anti-CD3ε BV605 (clone 145-2C11, Biolegend).…”

Frontline Science: Human bone cells as a source of IL-27 under inflammatory conditions: role of TLRs and cytokines

“…In these cells, induction of EBI3 and p28 is dependent on specific and distinct pathways and the expression of the 2 subunits of IL-27 can be dissociated. Whereas activation of EBI3 promoter involves NF-kB and PU.1, expression of p28 is induced at early times by NF-kB and requires several members of the IRF family (IRF1, IRF3, IRF7, and IRF9) and autocrine production of type I IFN for sustained expression [35][36][37][38][39]. Thus, cytokines or TLRs that activate NF-kB or MyD88/NF-kB pathway (TLR2, TLR4, TLR5, TLR7, TLR9) induce EBI3 expression, whereas those that activate specific IRFs (such as IFNs) or TRIF/IRF pathway (TLR3 and TLR4) are potent inducers of p28 expression [26,27,[40][41][42].…”