Abstract
The pathogenic effect of mutant HTT (mHTT) which causes Huntington disease (HD) are not restricted to nervous system. Such phenotypes include aberrant immune responses observed in the HD models. However, it is still unclear how this immune dysregulation influences the innate immune response against pathogenic infection. In the present study, we used transgenic Drosophila melanogaster expressing mutant HTT protein (mHTT) with hemocyte-specific drivers and examined the immune responses and hemocyte function. We found that mHTT expression in the hemocytes did not affect fly viability, but the numbers of circulating hemocytes were significantly decreased. Consequently, we observed that the expression of mHTT in the hemocytes compromised the immune responses including clot formation and encapsulation which lead to the increased susceptibility to entomopathogenic nematode and parasitoid wasp infections. In addition, mHTT expression in Drosophila macrophage-like S2 cells in vitro reduced ATP levels, phagocytic activity and the induction of antimicrobial peptides. Further effects observed in mHTT-expressing cells included the altered production of cytokines and activation of JAK/STAT signaling. The present study shows that the expression of mHTT in Drosophila hemocytes causes deficient cellular and humoral immune responses against invading pathogens. Our findings provide the insight into the pathogenic effects of mHTT in the immune cells.
Highlights
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an abnormal expansion of CAG trinucleotide in the Huntingtin gene
Our results suggest that the expression of mutant HTT (mHTT) in hemocytes does not directly affect survival but causes immune dysregulation, which leads to an impaired immune response against pathogenic invasion
In order to characterize the effects of mHTT in Drosophila hemocytes, we used a tissue-specific UAS-Gal4 system by expressing wild-type human HTT (Q20) or mutant HTT (Q93) under the control of a pan-neuronal driver, elav-gal4, or hemocyte drivers, hml-gal4, and he-gal4
Summary
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an abnormal expansion of CAG trinucleotide in the Huntingtin (htt) gene. Many clinical symptoms of HD are related to neuronal dysfunction, emerging evidence indicates that the expression of mHTT in non-neuronal cells of the brain or in the peripheral tissues contributes to the pathogenesis of HD [2]. Abnormal phenotypic effects caused by the dysfunction of non-neuronal cells have been described in cardiac cells, muscles, the endocrine system, adipose tissue, testes and immune cells of HD patients, and in mouse HD models [2, 3]. One recent study reported increased proliferation of a parasite, Toxoplasma gondii, in HD model mice, causing premature mortality and suggesting that expression of mHTT in immune cells may suppress immune responses [7]
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