BTK-NLRP3-Caspase1 and Gasdermin D-Caspase 11 pathways jointly drive neuroinflammation and functional impairments in a rat model of psychosocial stress

Common psychological disorders related to stress, depression and anxiety pose serious disease and economic burden globally and especially in lower and lower middle-income countries. Existing pharmacotherapies mostly target neurotransmitter systems and are partially effective across a range of diagnostic categories. However, it is also a long-standing finding that a low grade inflammation in persistently present in systemic circulation as well as in the brain in stress, depression and anxiety. Specifically, neuroinflammation driven by Interleukin-1β (IL-1β) a pleiotropic cytokine. has recently been the focus of keen interest in stress, depression and anxiety research. IL-1β is probably the most prominent proinflammatory cytokine in the brain and has been long associated with these conditions. We focus on molecules that cause IL-1β to be synthesized from its precursor, namely Caspase 1, through activation of a large multiprotein complex known as the NLRP3 inflammasome complex. Using two different rat models of physical and psychosocial stress, we validate our earlier findings of the induction of the BTK/NLRP3/Caspase 1 Canonical Pathway in stressed animals. We also show the involvement of Gasdermin D/Caspase11 driven non canonical pathway that contributes to enhanced leakage of IL-1β from cells through pyroptosis, in the absence of lytic cell death. Stressed rats display a robust neuroinflammatory phenotype, reduction in CA3 Hippocampal spine density, as well as number of mature mushroom spines, and functional impairments across multiple domains of behavior. Finally we employ two FDA approved drugs, Ibrutinib and Disulfiram to partially mitigate the neural, neuroinflammatory phenotype as well as behavioral dysfunctions, individually and in combination. The combination therapy proved to be more efficacious, suggesting a joint inhibition of the canonical and non canonical pathway mitigates the pathological as well as behavioral sequelae of psychosocial stress. Taken together our data provides robust preclinical data and argues for amelioration of the NLRP3 dependent IL-1β release to be considered as an alternative therapeutic strategy in stress, depression and anxiety.