Tick Salivary Sialostatin L Represses the Initiation of Immune Responses by Targeting IRF4-Dependent Transcription in Murine Mast Cells

Abstract

Co-evolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. Herein, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells while degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1 receptor-deficient mast cells exhibit strong impairment in IL-9 production demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9 suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction of asthma symptoms demonstrating the immunosuppressive potency of tick-derived molecules.

All For One and One For All on the Tick–Host Battlefield

“…A follow-up study showed that SialoL also inhibited proliferation of CD4+ T helper cells, dendritic cell (DC) maturation, and the production of proinflammatory cytokines [19]. It was later shown that SialoL diminished interleukin-9 (IL-9) production in Th9 lymphocytes and mast cells [20, 21]. Finally, SialoL impaired production of interferon-β (IFN-β) in DCs activated by Borrelia burgdorferii spirochetes [22].…”

For Whom the Bell Tolls (and Nods): Spit-acular Saliva

“…Inappropriate inflammation is also the cause for several sterile diseases including asthma, inflammatory bowel and autoimmune diseases, chronic inflammation resulting from long-term exposure to irritants, and cancer growth encouraged by immune cell infiltrates [70,78–83]. Furthermore, detrimental outcomes can result from an inflammatory response to an injury such as atherosclerosis or a brain aneurysm [84].…”

“…The precise inhibition mechanisms by SL and SL2 have not been thoroughly characterized. However, a recent study showed that SL inhibits the production of IL-1β and the transcription factor IRF4 in mast cells, which directly binds the promoter of il-1β [70]. This suggests that SL inhibits pro-inflammatory cytokine production at the RNA level by interfering with transcription factors [70].…”

“…However, a recent study showed that SL inhibits the production of IL-1β and the transcription factor IRF4 in mast cells, which directly binds the promoter of il-1β [70]. This suggests that SL inhibits pro-inflammatory cytokine production at the RNA level by interfering with transcription factors [70]. These studies are among the few that have parsed out specific effector compounds in tick saliva that affect TLR pathways.…”

Peptidase inhibitors in tick physiology

“…Tryptogalinin, an I. scapularis salivary Kunitz-type inhibitor, inhibits -tryptase, trypsin, -chymotrypsin, plasmin, matriptase and elastase, showing a potential broad effect against mast cell proteins and other host enzymes (Valdes et al, 2013). Furthermore, I. scapularis sialostatin L affects mast cell activation, resulting in immunosuppression (Klein et al, 2015).…”