Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye

Abstract

Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge due to incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or non-infectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoceptor retinoid binding protein (IRBP) in the presence of the adjuvant CFA. EAU manifests as posterior ocular inflammation consisting of vasculitis, granulomas, retinal damage and invasion of self-reactive T cells, which are key clinical features of human uveitis. Our studies uncover Card9 as a critical genetic determinant for EAU. Card9 was responsible for Th17 polarization and Th17-associated antigen-specific responses, but not Th1-associated responses. Nonetheless, Card9 expression was essential for accumulation of both lineages within the eye. Consistent with its recently identified role as an intracellular signaling mediator for C-type lectin receptors (CLRs), a Card9-dependent transcriptional response in the neuroretina was observed involving genes encoding the CLRs Dectin-1, Dectin-2 and Mincle. Genetic deletion of these individual CLRs revealed an essential role for Mincle. Mincle activation was sufficient to generate the EAU phenotype, and this required activation of both Syk and Card9. In contrast, Dectin-1 contributed minimally and a possible repressive role was shown for Dectin-2. These findings extend our understanding of CLRs in autoimmune uveitis. The newly identified role of Mincle and Syk/Card9-coupled signaling axis in autoimmune uveitis could provide novel targets for treatment of patients with ocular inflammatory disease.

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

“…5). This effect was only partially lost in LPS‐primed BMDC from TLR4 knockout mice, indicating that the M. tuberculosis ligands in this extract were acting by additional pathways, such as TLR2 and Dectin‐1 48. These data for the first time show that LPS (endotoxin) “heterotolerance” or “crosstolerance” to M. tuberculosis ligands, i.e.…”

“…Mycobacterium tuberculosis activates DC through several ligands including TLR2 and Dectin‐1, and less so TLR4 with downstream activation of the inflammasome and secretion of IL‐1 β . Furthermore, Dectin‐1, Mincle and signalling through the Syk/Card 9 complex are required for induction of EAU by way of IRBP:CFA 48, 49. As signalling by the IL‐1 receptor has recently been shown to be critical for the induction of EAU,50 it is a distinct possibility that LPS‐primed BMDC prevent IRBP:CFA‐induced EAU by blocking BMDC inflammasome activation and IL‐1 β production.…”

“…We show that upLPS‐primed BMDC are endotoxin homotolerant (ET‐BMDC) and further show that they are heterotolerant to M. tuberculosis protein extract in that they are (i) susceptible to apoptosis45, 46, 47 (confirmed here) through a CD14/nuclear factor of activated T cells (NFATc)‐associated mechanism, and (ii) fail to secrete IL‐1 β on exposure to M. tuberculosis extract. As M. tuberculosis mediated C‐type lectin receptor signalling via the Syk/CARD‐9 complex,48 a major route for inflammasome activation, has been shown to be an essential mediator of IRBP‐CFA‐induced EAU,48, 49 we propose that inhibition of IL‐1 β secretion is one mechanism whereby heterotolerant LPS‐primed BMDC promote immunological tolerance. We also show that additional mechanisms are at play including induction of BMDC apoptosis as well as disruption of NF‐ κ B and IRF3‐mediated cytokine secretion.…”

Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate

“…Recently published results indicate that signaling through Mincle plays a role in obesity-induced adipose tissue inflammation and the subsequent adipose tissue fibrosis (28). Recently, an essential role of Mincle signaling through the Syk/Card9 axis in the development of autoimmune eye inflammation in a model of experimental autoimmune uveoretinitis was revealed (29). It was shown that Mincle signaling promotes pancreatic oncogenesis, whereas the deletion of Mincle protects against oncogenesis (30).…”

The essential function of CARD9 in diet‐induced inflammation and metabolic disorders in mice

“…Recently, studies have focused on defining the precise molecular mechanism of CARD9 signalling and exploring its role in the development of non‐infectious disease including cardiovascular diseases 9, 10. Obesity and type 2 diabetes (T2D) have become the leading health problem in the world.…”