The complex link of IL-1RAcP in engendering neuroprotection from alcohol-induced prefrontal cortical dysfunction in rhesus macaques and mice

A recent report by Liss and colleagues in Brain Behavior and Immunity (Liss et al., 2026) provided first-of-its kind data that characterized the persistent actions of the proinflammatory cytokine, interleukin-1β (IL-1β) in generating dysfunction in the prefrontal cortex (PFC) from alcohol use disorder (AUD) in mice and, and uniquely, in monkeys. Sex differences were reported showing a vulnerability of adverse brain IL-1 signaling in males exposed to alcohol. Adult male and female mice that developed a preference for chronic alcohol drinking at moderate levels demonstrated reduced performance on spatial learning memory, a task that is supported by the function of the PFC. While cognitive tasks were not assessed in alcohol drinking rhesus macaques, gene expression analyses of components related to the IL-1 receptor complex corroborated findings in mice.

IL-1 is well-characterized to play diverse and critical roles in the development of inflammatory responses within the central nervous system (CNS) encompassing the innate and adaptive immune response to CNS trauma, infection and stress challenges (Kono et al., 2014; Srinivasan et al., 2004). However, accumulating evidence supports that IL-1 serves a protective, physiological role to modulate neuronal activity and enhance survival (Gosselin et al., 2013). The dichotomy of IL-1 actions is based on the discovery of factors that interact with its receptor, the IL-1 type 1 receptor (IL-1R), expressed on the surface of a variety of non-neuronal cells as well as neurons in the CNS, resulting in subsequent recruitment and heterodimerization of IL-1 accessory protein (IL-1RAcP) essential for triggering intracellular signaling pathways (Cullinan et al., 1998). Thus, IL-1 stimulates the formation of a protein complex such that IL-1RAcP is recruited to the IL-1R, initiating the assembly of several downstream adaptor molecules that ultimately generate inflammatory responses (e.g. MyD88, IRAK1, IRAK2, PI 3-kinase) (Reddy et al., 2004).

However, IL-1RAcP occurs in two isoforms. IL-1RAcP is expressed throughout the body and the CNS, while an isoform of AcP derived from alternative splicing in a key region of exon 12, referred to as IL-1RAcPb (Smith et al., 2009), is expressed mostly in neurons of the CNS with robust expression in regions such as the prelimbic cortex, whole hippocampus, and dentate gyrus. However, IL-1RAcPb is not expressed in non-neurons (Nemeth et al., 2024). In addition to its distinct anatomical distribution, IL-1RAcPb demonstrates functional differences from IL-1RAcP. Specifically, while IL-1RAcPb interacts with IL-1 and the IL-1R, the downstream cellular canonical IL-1 responses typically generated following recruitment of IL-1RAcP to IL-1R are not initiated (Smith et al., 2009). Upon further examination of the in vivo function of IL-1RAcPb, mice deficient in IL-1RAcPb expression reveal an intact peripheral IL-1 response but are more vulnerable to a local CNS inflammatory challenge and suffered enhanced neuronal degeneration as a consequence of such challenge. Based on the critical impact that these accessory protein isoforms exert on the cellular response to IL-1, characterizing their expression along with associated components of the IL-1 complex is necessary to gain a complete picture of the IL-1 response to challenges in the CNS. More specifically, the actions of IL-1 can now include the possibility of a switch from the detrimental and damaging effects of IL-1R signaling, to a modulatory action that reduces an unchecked inflammatory IL-1 response. One such candidate could be AcPb capable of modulating IL-1-mediated CNS responses between neuronal inflammation and neuronal health (Smith et al., 2009).

Given this evolving and intriguing evidence for the complementary actions of IL-1 in the CNS, Liss and colleagues (Liss et al., 2026) further examined the potential role of IL-1RAcPb as a neuroprotective component in the IL-1R signaling pathway. Specifically, how might a binge-drinking rodent model and a chronic alcohol exposure model in rhesus monkeys impact IL-1R signaling via alterations in IL-1RAcP gene expression and its actions that may influence cognitive function. Strikingly, increases in gene expression of neuroprotective IL-1RAcPb in the female mouse PFC and rhesus macaque dlPFC was identified, which the authors suggest generates an overall neuroprotective phenotype. This report is the first demonstration of similar, protective Il-1R responses in alcohol drinking mice and monkeys, such results show that the function of IL-1RAcP and IL-1RAcPb are highly conserved.

In line with the potential adaptive function of IL-1RAcPb in neurons, Liss and colleagues (Liss et al., 2026) additionally report data from the current report utilizing slice electrophysiology experiments with pharmacological manipulation to prevent IL-1R from interacting with a key downstream factor (MyD88) that is required for inflammatory actions. Examining mPFC GABA synapses, female mice appear to be less sensitive to the detrimental effects of IL-1β, as they preferentially express IL-1RAcPb (similarly observed via gene expression analysis of rhesus macaque dlPFC), reducing the recruitment of downstream inflammatory factors under basal conditions or following alcohol exposure. Conversely, neurons from male mice treated with alcohol demonstrated altered IL-1R1 signaling mediated by the recruitment MyD88 resulting in mPFC neuronal inhibition, which the authors speculate may disrupt its circuit communication with other brain regions. Thus, the results support increased neuroprotection in females, contributing to the synaptic resilience from alcohol exposure while alcohol in males biases IL-1/IL-1R pathway to proinflammatory signaling. Clinically, the findings may provide a framework to target/enhance the actions of IL-1RAcPb as a therapeutic to reduce cognitive dysfunction and neuronal toxicity from AUD.

Data availability

This is a commentary of a prior published body of work