Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections

Abstract

Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.

Siglec-H-/- Plasmacytoid Dendritic Cells Protect Against Acute Liver Injury by Suppressing IFN-γ/Th1 Response and Promoting IL-21+ CD4 T Cells

“…This was consistent with observations previously reported in SH-null pDCs from lymphoid tissues. 32 , 41

Figure 9 SH loss in pDCs affects molecules associated with APC functions. Mean fluorescence intensity (MFI) of ( A ) MHC-II, ( B ) CD86, ( C ) CCR9, and ( D ) CD40 in pDCs isolated from the liver of naive WT and SH KO mice.

…”

“…Specific inhibition of SH in pDCs may seem a beneficial therapeutic approach to protecting against ALI; it is important to point out that SH-deficient pDCs with elevated IFN-I production and impaired APC maturation may potentially aggravate pDC-induced chronic inflammatory diseases including systemic lupus erythematosus, 36 , 60 psoriasis, 61 virus infection, 23 , 24 , 41 liver fibrosis, and cancer.…”

The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond

“…Indeed, mice deficient in SiglecH, a C-type lectin expressed on pDCs that inhibits IFN production downstream of TLR7/9 recognition [73], exhibit prolonged IFN responses during persistent MCMV infection and develop an IFN-I-dependent severe form of systemic lupus-like autoimmune disease [141]. However, this was not the case when these mice were infected with IAV or LCMV clone 13 [142].…”

Toll-like receptors 7 and 9 regulate the proliferation and differentiation of B cells in systemic lupus erythematosus

“…Studies show that overactivation or impaired function of the TLRs that detect nucleic acids, TLR7 and TLR9, induces dysfunction of innate immunity and breakdown of immune tolerance, which can lead to the occurrence of autoimmunity ( 7 , 8 ). Both TLR7 and TLR9 are strongly associated with interferon (IFN) production by plasmacytoid dendritic cells (pDCs) ( 9 ). In addition, they are also expressed in B cells, wherein they play crucial functions ( 10 ).…”