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  • Of note CS associated lung injury


    Of note, CS-associated lung injury is closely linked with augmented influx of macrophages that subsequently intensify the lung injury [34,47] while macrophage depletion alleviates CS-induced pulmonary inflammation via reducing cytokines and chemokine production in BALF [48]. Similar effect has been observed from PGD2/CRTH2 activated macrophages in LPS-induced ALI models [22] while the genetic sorafenib tosylate of CRTH2 reduced the production of TNF‑α in sepsis, a common cause of ALI [31]. Nevertheless, macrophage-derived TNF‑α [49,50] and IL‑1β [51], early response cytokines to lung injury, stimulate the production of IL-6 [52] and IL-8 [53]. Released pro-inflammatory cytokine (TNF‑α, IL‑1β, IL-6) [54,55] particularly IL-8 [56,57] triggers the inappropriate neutrophils migration across the endothelial barrier, that eventually exaggerates the lung injury, while genetic ablation of CXCR2, IL-8 receptor beta, showed protective response against CS-induced lung injury [58]. Notably, elevated expression levels of TNF‑α, IL‑1β, IL-6, and IL-8 have been observed in various CS-induced in vivo and in vitro lung injury models [[59], [60], [61], [62], [63]] while inhibition of pro-inflammatory cytokines and chemokines production proved effective in CS-induced lung injury [64,65]. Moreover, IL-10 has been reported as a potent immunomodulatory cytokine in counterbalancing the pro-inflammatory response. Decreased IL-10 level has been observed in ALI mice [66] while IL-10 treatment attenuated the severity of ALI [67]. Consistent with previous studies, we observed augmented infiltration of macrophages in BALF, overexpression of pro-inflammatory cytokines and chemokines and decreased expression of IL-10 while CRTH2 antagonism with CT‑133 altered the inappropriate recruitment of alveolar macrophages, alleviated the uncontrolled overexpression of pro-inflammatory cytokines and chemokines and enhanced the IL-10 production in vivo and in vitro.
    Introduction Several psychiatric and neurological disorders are associated with cognitive dysfunction, including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorders, bipolar disorder, depression and schizophrenia [1], [2], [3]. Many pathological factors, such as stress and neuroinflammation, also contribute to cognitive dysfunction [4], [5]. Therefore, it is important to elucidate the molecular mechanisms that underlie cognitive dysfunction to develop therapies for various psychiatric and neurological disorders. Neuroinflammation plays an important role in cognitive dysfunction [5]. Inflammatory cytokines, such as interleukin-1β and tumor necrosis factor α, contribute to cognitive dysfunction [6], [7]. Cyclooxygenase (COX), a rate-limiting enzyme in prostanoid synthesis, also plays a role in neuroinflammation-mediated cognitive dysfunction [8]. Previous studies have demonstrated that COX activity is increased in the platelets of patients with schizophrenia [9] and that COX-2 is upregulated in the hippocampus of Alzheimer’s disease patients [10]. Therefore, the COX pathway and its downstream signaling molecule prostanoid have emerged as main players involved in cognitive dysfunction in pathological conditions. Prostanoids, such as prostaglandins (PGs) (PGD2, PGE2, PGF2α and PGI2) and thromboxane A2, which are synthesized through the sequential actions of COX and their respective synthases, function through their cognate G-protein-coupled receptors [8], [11]. Therefore, to fully understand the roles of prostanoid signaling in neuroinflammation-mediated cognitive dysfunction, it is important to dissect the role of each prostanoid and its receptor in pathological conditions. To date, there is limited evidence regarding the specific prostanoids and their receptors that are related to cognitive dysfunction in pathological conditions. Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) is a second PGD2 receptor with roles in peripheral tissue. CRTH2-mediated signaling promotes leukocyte migration [12], [13] and exacerbates allergic rhinitis [14], [15]. In addition to its peripheral roles, we have recently demonstrated that CRTH2-mediated signaling mediates emotional impairment in a lipopolysaccharide (LPS)- and tumor-induced sickness behavior model, and depression-related behavior in animal models of human depression [16], [17]. In addition, we have demonstrated that the blockade of CRTH2-mediated signaling suppresses LPS- and tumor-induced decreases in novel object investigation behavior, which indicates a loss of interest rather than a decline in cognition [16]. These findings suggest that CRTH2-mediated signaling plays an important role in emotional behavior and have led us to investigate the potential role of CRTH2-mediated signaling in other higher brain functions, such as cognition.