Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus–like inflammation

Abstract

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

“…The mechanism by which MMP-7 inhibits inflammation remains to be elucidated, but it could be related to the degradation of FasL as well, because FasL also participates in the regulation of inflammation by an apoptosis-independent mechanism. 47,48 Furthermore, MMP-7 appears to promote anti-inflammatory M2 macrophage polarization, while it has no effect on proinflammatory M1 macrophage activation (Supplementary Figure S3). This could be another mechanism by which MMP-7 elicits its anti-inflammatory action.…”

T cells instruct myeloid cells to produce inflammasome-independent IL-1β and cause autoimmunity

“…The existence of diverse receptors for T cell-induced pro-IL-1β is parallel to the ability of different innate recognition receptors to upregulate pro-IL-1β. Fas signaling has been reported to induce the transcription of pro-IL-1β in TLR9-dependent autoimmune inflammation 39 . We did not find evidence for a role for Fas in the synthesis of pro-IL-1β, suggesting that Fas could contribute to the synthesis of IL-1β only in the context of canonical PRR ligands.…”

Advances in Cutaneous Lupus Erythematosus and Dermatomyositis: A Report from the 4th International Conference on Cutaneous Lupus Erythematosus—An Ongoing Need for International Consensus and Collaborations

“…TLR9-deficient mice exhibit more extensive B-cell activation than TLR9sufficient littermates and are also distinguished by high numbers of ovalbumin-specific Tbet (T-box, expressed in T cells) þ , IFN-g þ , Fas ligand-expressing T helper type 1 cells. Contrary to most models of SLE, the DO11/TLR9-deficient mice also develop skin lesions that are very similar to human CLE (Mande et al, 2018).…”