Chronic allodynia, characterized by aversive nociceptive and emotional alterations, is featured with a painful response to an innocuous stimulus (Melvin et al., 2025). Its prevalence varies from 10 % to 60 % of the population in different areas (Phillips, 2009). As a major issue of disabled individuals, chronic allodynia persists so long even without external nociceptive stimuli that it causes both tremendous physical and psychological stresses, in which mechanical allodynia is the most notorious (Li and Hu, 2016; Bidve et al., 2020). Within the central nervous system (CNS), microgliosis and astrogliosis drive neuroinflammation to regulate neural activity to sustain chronic allodynia (Ji et al., 2018). Because of aberrant neuroinflammation, oxidative stress induced alteration of neuronal circuitry and synaptic plasticity, thereby causing maladaptive neuroplasticity of CNS (Sharma et al., 2018). Due to the poor efficacy and short duration of local anesthesia, current therapeutic options of chronic allodynia are CNS-targeted, and nanomedicine is under investigation to overcome the problem (Bidve et al., 2020; Gadepalli et al., 2024). However, the CNS-targeted therapy elicits several adverse effects, and chronic allodynia is often recalcitrant to traditional therapy despite the use of potent medication (Tajerian et al., 2014). In response to inflammation, thymic stromal lymphopoietin (TSLP) is highly expressed within the CNS. Through acting on the TSLP receptor (TSLPR) to initiate signal transducer and activator of transcription (STAT) signaling, TSLP influences the innate and adaptive immune systems (Cultrone et al., 2013). It has been reported that TSLP/TSLPR signaling arises in the cortex of rats following stroke and that a lack of TSLPR alleviates autoimmune encephalitis by decreasing the inflammasome (Yu et al., 2019, 2022). Moreover, TSLP within the dorsal root ganglion causes mechanical allodynia by regulating T cells (Ino et al., 2023). Our earlier studies revealed that TSLP/TSLPR/STAT5 signaling was activated in the mouse somatosensory cortex after the administration of bleomycin, which led to chronic mechanical nociception (Lu et al., 2024a). Therefore, blockade of TSLP signals is a potential strategy to control chronic allodynia.

IL22 is produced mainly by Th cells, such as Th22, Th17, and type 3 innate lymphoid cells, and has diverse influences on various diseases to maintain hemostasis (Seth and Dubey, 2023). It elicits a protective effect to preserve epithelial integrity in mucosal disorders, whereas it induces inflammation in atopic dermatitis, psoriasis and allergic airway disease (Liang et al., 2020). Upon binding on the IL22 receptor (IL22R), the phosphorylation of Janus kinases (JAKs) and tyrosine kinases (TYKs) activate STAT (STAT1 or STAT3). The protective effect of IL22 is largely mediated by STAT3, whereas the inflammatory effect is mediated by STAT1 (Saxton et al., 2021). Depending on the activation of STAT3, IL22 inhibits mucosal cell apoptosis to preserve intestinal integrity via anti-apoptotic factors (Zhao et al., 2025; Arnhold et al., 2024). The definite effect of IL22 on nerve systems remains inconclusive. Scarce studies reported that the aberrant downstream JAK/STAT signaling in CNS mediates neuroinflammation, thereby causing CNS dysregulation and altering the state of neurons and glial cells (Nevado-Holgado et al., 2019). IL22 can protect human astrocytes against apoptosis through anti-apoptotic factors in multiple sclerosis although the expression of IL22 has been reported to be correlated with the progression of disease (Perriard et al., 2015). In mice with experimental autoimmune uveitis, IL22 administration ameliorated the death of retinal ganglion cells by regulating T-reg cells (Mattapallil et al., 2019). Likewise, IL22 improved the infarct size and neurological deficits in mice with cerebral ischemia reperfusion injury by STAT3 signaling (Dong et al., 2021). IL22 potentially has both neurotoxicity and neuroprotective properties on neurons and glial cells. Currently, the role of IL22 in chronic allodynia remains unclear. In addition, the role of TSLP in regulating the signals of IL22 in the brain and their crosstalk with respect to chronic allodynia is unsettled.

Our current study aimed to investigate the potential of modulating TSLP expression for treating chronic allodynia and elucidate its underlying mechanisms associated with IL22. We explored the therapeutic efficacy and mechanism of TSLP deficiency in a mouse model of chronic allodynia induced by bleomycin administration through behavior assessment, immunofluorescence staining, and western blot analysis. Microgliosis, astrogliosis and neuron loss were also examined. Likewise, differentiated human SH-SY5Y cells were created to clarify the neuroprotective effects of TSLP refinement against hydrogen peroxide (H2O2)-induced neurotoxicity.