AUTHOR=Zhang Linlin , Bang Sangsu , He Qianru , Matsuda Megumi , Luo Xin , Jiang Yong-Hui , Ji Ru-Rong 

TITLE=SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1124356

DOI=10.3389/fimmu.2023.1124356

ISSN=1664-3224

ABSTRACT=<p>Excessive inflammation has been implicated in autism spectrum disorder (ASD), but the underlying mechanisms have not been fully studied. SHANK3 is a synaptic scaffolding protein and mutations of <italic>SHANK3</italic> are involved in ASD. Shank3 expression in dorsal root ganglion sensory neurons also regulates heat pain and touch. However, the role of Shank3 in the vagus system remains unknown. We induced systemic inflammation by lipopolysaccharide (LPS) and measured body temperature and serum IL-6 levels in mice. We found that homozygous and heterozygous <italic>Shank3</italic> deficiency, but not <italic>Shank2</italic> and <italic>Trpv1</italic> deficiency, aggravates hypothermia, systemic inflammation (serum IL-6 levels), and sepsis mortality in mice, induced by lipopolysaccharide (LPS). Furthermore, these deficits can be recapitulated by specific deletion of <italic>Shank3</italic> in Nav1.8-expressing sensory neurons in conditional knockout (CKO) mice or by selective knockdown of <italic>Shank3</italic> or <italic>Trpm2</italic> in vagal sensory neurons in nodose ganglion (NG). Mice with <italic>Shank3</italic> deficiency have normal basal core temperature but fail to adjust body temperature after perturbations with lower or higher body temperatures or auricular vagus nerve stimulation. <italic>In situ</italic> hybridization with RNAscope revealed that <italic>Shank3</italic> is broadly expressed by vagal sensory neurons and this expression was largely lost in <italic>Shank3</italic> cKO mice. Mechanistically, <italic>Shank3</italic> regulates the expression of <italic>Trpm2</italic> in NG, as <italic>Trpm2</italic> but not <italic>Trpv1</italic> mRNA levels in NG were significantly reduced in <italic>Shank3</italic> KO mice. Our findings demonstrated a novel molecular mechanism by which Shank3 in vagal sensory neurons regulates body temperature, inflammation, and sepsis. We also provided new insights into inflammation dysregulation in ASD.</p>