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Inappropriate accumulation of alveolar macrophages (AMs) and subsequent excessive production of immune responses play critical roles in the pathogenesis of acute lung injury (ALI), but the core negative regulators governing innate signalling in AMs are ill defined. We have previously shown that single immunoglobin IL‐1 receptor‐related protein (SIGIRR), a negative regulator of IL‐1 receptor and Toll‐like receptor signalling, inhibits lipopolysaccharide (LPS)‐induced inflammatory responses in AMs. To address the biological relevance of SIGIRR in vivo, we generated a murine ALI model via intratracheal instillation of LPS. Intriguingly, SIGIRR expression was observed to be decreased in resident and recruited macrophages during ALI. This decrease was associated with parallel induction in CD18 protein levels in LPS‐challenged lung tissues. Through intranasal injection of SIGIRR lentiviral particles studies, we showed that the overexpression of SIGIRR attenuated recruitment of macrophages and neutrophils, decreased production of inflammatory cytokines and ameliorated pathological changes in lungs. Whilst exploring the basis for this phenotype, SIGIRR was found to be coexpressed with CD18 in AMs, and SIGIRR potentiated the instability of CD18 protein via enhancement of its ubiquitination and proteasome degradation. Conversely, by using CD18−/− mice, we further observed that CD18 deletion completely abolished the therapeutic effects of overexpression of SIGIRR on LPS‐induced ALI. Mover, overexpression of CD18 in AMs promoted adhesion to ECM components, enhanced TLR4‐mediated inflammasome activation and thereby potentiated IL‐1β production. These data collectively identify SIGIRR/CD18 as a key negative regulatory circuit maintaining innate immune homeostasis in AMs along the pathogenesis of ALI. [ABSTRACT FROM AUTHOR]

Introduction: Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4–ALK) is identified as an important pathogenic factor in patients with non-small-cell lung cancer (NSCLC) and could induce a stem-like phenotype in NSCLC cells. Crizotinib is commonly used for EML4–ALK+ NSCLC treatment, but its acquired resistance results in tumor recurrence. Long intergenic noncoding RNA, regulator of reprogramming (lincROR) is related to the acquisition and maintenance of self-renewal and stemness features of cancer stem cells. It has been documented that lincROR is implicated in chemoresistance. However, the correlations of lincROR and EML4–ALK in stem cell-like properties and of lincROR and crizotinib resistance in NSCLC cells are yet to be elucidated. Patients and methods: In the present study, we investigated the expression profile of lincROR in EML–ALK NSCLC tissues, and the potential role of lincROR in prognosis was then analyzed. Subsequently, its association with stem cell-like properties of EML–ALK+ NSCLC cells was determined. Furthermore, the correlation of lincROR with crizotinib and the effects of lincROR and crizotinib on cell viability of EML4–ALK+ NSCLC cells were all explored. Results: The results showed that lincROR expression was upregulated in EML4–ALK+ NSCLC tissues relative to EML4–ALK− NSCLC tissues. Low-expressed lincROR was related to a favor-able prognosis of patients with EML–ALK NSCLC. lincROR overexpression could enhance the stemness features of EML–ALK+ NSCLC cells which were repressed by ALK knockdown. Conclusion: We found that lincROR expression was significantly inhibited because of the increased concentration of crizotinib in EML4–ALK+ NSCLC cells. Furthermore, lincROR overexpression increased cell viability of EML4–ALK+ NSCLC cells, which was impaired by crizotinib. Conjointly, these results suggested the important role of lincROR in EML–ALK+NSCLC. lincROR may serve as a potential therapeutic target to overcome chemotherapy resistance in EML–ALK+ NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase ( EML4-ALK ) is identified as an important pathogenic factor in patients with non-small-cell lung cancer (NSCLC) and could induce a stem-like phenotype in NSCLC cells. Crizotinib is commonly used for EML4-ALK + NSCLC treatment, but its acquired resistance results in tumor recurrence. Long intergenic noncoding RNA, regulator of reprogramming (lincROR) is related to the acquisition and maintenance of self-renewal and stemness features of cancer stem cells. It has been documented that lincROR is implicated in chemoresistance. However, the correlations of lincROR and EML4-ALK in stem cell-like properties and of lincROR and crizotinib resistance in NSCLC cells are yet to be elucidated., Patients and Methods: In the present study, we investigated the expression profile of lincROR in EML-ALK NSCLC tissues, and the potential role of lincROR in prognosis was then analyzed. Subsequently, its association with stem cell-like properties of EML-ALK + NSCLC cells was determined. Furthermore, the correlation of lincROR with crizotinib and the effects of lincROR and crizotinib on cell viability of EML4-ALK + NSCLC cells were all explored., Results: The results showed that lincROR expression was upregulated in EML4-ALK + NSCLC tissues relative to EML4-ALK - NSCLC tissues. Low-expressed lincROR was related to a favorable prognosis of patients with EML-ALK NSCLC. lincROR overexpression could enhance the stemness features of EML-ALK + NSCLC cells which were repressed by ALK knockdown., Conclusion: We found that lincROR expression was significantly inhibited because of the increased concentration of crizotinib in EML4-ALK + NSCLC cells. Furthermore, lincROR overexpression increased cell viability of EML4-ALK + NSCLC cells, which was impaired by crizotinib. Conjointly, these results suggested the important role of lincROR in EML-ALK + NSCLC. lincROR may serve as a potential therapeutic target to overcome chemotherapy resistance in EML-ALK + NSCLC., Competing Interests: Disclosure The authors report no conflicts of interest in this work.