Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes

Abstract

SummaryDNAX-activation protein 12 (DAP12), a transmembrane adapter, plays a major role in transducing activation signals in natural killer cells and various myeloid cells. Quantitative RT-PCR detected in normal mouse eyes considerable levels of DAP12 and multiple DAP12-coupled receptors, in particular TREM-1, Clec5a and SIRPb1. The role of DAP12 and its receptors in experimental autoimmune diseases has been controversial. Here, we analysed the effect of DAP12 deficiency on the capacity of mice to mount immunopathogenic cellular responses to the uveitogenic ocular antigen and interphotoreceptor retinoid-binding protein (IRBP), and to develop experimental autoimmune uveitis (EAU). Surprisingly, sequential analysis of EAU in mice deficient in DAP12 in two different animal facilities at first revealed enhanced disease as compared with wild-type mice, but when these mice were re-derived into a second, cleaner, animal facility, the response of control mice was essentially unchanged, whereas the DAP12 null mice were markedly hyporesponsive relative to controls in the new facility. Accordingly, when stimulated in vitro with IRBP, lymphocytes from the DAP12-deficient mice housed in the two facilities proliferated and produced opposite profiles of pro-inflammatory and antiinflammatory cytokines, compared with their controls. These findings therefore demonstrate that the effects of DAP12 deficiency on development of autoimmune disease are dramatically affected by environmental factors.

Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental autoimmune uveitis

“…Surprisingly, a recent brief report has suggested that C3aR/ C5aR KO mice with the same C57BL/6 background did not show any defect in developing EAU compared with control WT mice [17]. The exact reasons behind this apparent discrepancy are unclear; however, housing conditions could have played a role, because environmental factors, including the gut microbiome, has been found to affect the pathogenesis of many disease models, including EAU [46][47][48]. Also, the histopathological analysis was the only assay used to compare the severity of EAU between WT and KO mice for the whole study [17].…”

TREM2 in Neurodegenerative Diseases

“…Whether DAP12 serves to activate or inhibit the immune response depends on the receptor it is associated with, the stimulus used to activate that receptor and the strength of that stimulus. It may also depend on availability of different downstream signaling components locally at the membrane, their relative expression in the cell [ 262 ] or other environmental factors [ 271 ]. Much of the signaling data thus far was performed in cultured osteoclasts, and future studies may find that other cell types use distinct signaling mechanisms.…”

Digoxin Inhibits Induction of Experimental Autoimmune Uveitis in Mice, but Causes Severe Retinal Degeneration

“…33 and 34) and it is assumed that the microbiome of the mice in the present study was different from that of the mice in the cited study, 29 since the mice of the two studies were housed in different animal facilities. Indeed, we have shown in another study that mice of the same line differ in their EAU development when housed in different facilities 35 and microbial products were found to facilitate ocular autoimmune processes. 36 …”