Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs

BackgroundPaclitaxel is commonly used as a cancer chemotherapy drug that frequently causes peripheral neuropathic pain. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein, and caspase-1, which functions to switch on the inflammatory process and the release of interleukin-1β. Growing evidences have supported that peripheral interleukin-1β is critical in enhancing paclitaxel-induced neuropathic pain. However, whether activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain is still unclear.ResultsPaclitaxel induced mechanical allodynia of rats from day 3 and worsened gradually till 3 weeks after injection. Paclitaxel resulted in expression of NLRP3 and activated fragments of caspase-1 and interleukin-1β in L4-6 dorsal root ganglia and sciatic nerve three weeks after injection, indicating activation of NLRP3 inflammasome. The expression of NLRP3 was located in CD68-labeled macrophages infiltrating in L4-6 dorsal root ganglia and sciatic nerve, and paclitaxel increased the expression of NLRP3 in macrophage. Moreover, the paclitaxel elicited mitochondria damage, which became swollen and enlarged in macrophages and axons of sciatic nerve three weeks after injection. In vitro, paclitaxel increased the number of damaged mitochondria and mitochondrial reactive oxygen species production in the rat alveolar macrophage cell line NR8383. The administration of a non-specific reactive oxygen species scavenger, phenyl-N-tert-butylnitrone, markedly alleviated mechanical allodynia and inhibited the activation of NLRP3 inflammasome in L4-6 dorsal root ganglia and sciatic nerve of the paclitaxel-induced neuropathic pain model.ConclusionsPaclitaxel induced mechanical allodynia and activation of NLRP3 inflammasome in infiltrated macrophages of L4-6 dorsal root ganglia and sciatic nerve. Paclitaxel elicited mitochondria damage and reactive oxygen species production may result in activation of NLRP3 inflammasome in peripheral nerve, which contributes to paclitaxel-induced neuropathic pain.

show abstract

“… 37 It suggested that activation of the NLRP3-dependent inflammasome might be derived from the macrophages. 35 , 38 …”

Section: Discussionmentioning

confidence: 99%

Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that treatment of mice with doxorubicin induced IL-1β release from bone marrowderived macrophages via activation of the NLRP3 inflammasome [36,37]. Recently, Kobayashi et al suggested that NLRP3 plays a role in doxorubicin-induced cardiotoxicity [38].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Kim

Park

et al. 2018

Kidney Blood Press Res

View full text Add to dashboard Cite

Background/Aims: Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. Methods: Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. Results: A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1β was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91^phox, p47^phox, and p67^phox in rat kidneys with doxorubicin nephropathy. Conclusion: NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.

show abstract

“…Common inflammatory mediators, including TGFβ, TNFα, PGE2, HGF, and IL1β, drive chronic obstructive pulmonary disease, such as pulmonary fibrosis, and emphysema. These mediators also play essential roles in the regulation of bone marrow homeostasis, affecting immune cell survival, migration, proliferation, and differentiation [125–130]. Thus, it is possible that these molecules, altered in these pulmonary disorders, participate in bone marrow alterations that will affect lung cancer development.…”

Section: Perspectives / Future Directionsmentioning

confidence: 99%

Cross-talk between lung cancer and bones results in neutrophils that promote tumor progression

Azevedo

Paiva

Santos

et al. 2018

Cancer Metastasis Rev

View full text Add to dashboard Cite

Lung cancer is the leading cause of cancer mortality around the world. The lack of detailed understanding of the cellular and molecular mechanisms participating in the lung tumor progression restrains the development of efficient treatments. Recently, by using state-of-the-art technologies, including in vivo sophisticated Cre/loxP technologies in combination with lung tumor models, it was revealed that osteoblasts activate neutrophils that promote tumor growth in the lung. Strikingly, genetic ablation of osteoblasts abolished lung tumor progression via interruption of SiglecF-expressing neutrophils supply to the tumor microenvironment. Interestingly, SiglecF neutrophil signature was associated with worse lung adenocarcinoma patients outcome. This study identifies novel cellular targets for lung cancer treatment. Here, we summarize and evaluate recent advances in our understanding of lung tumor microenvironment.

show abstract

Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs

Cited by 41 publications

References 54 publications

Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain

Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Cross-talk between lung cancer and bones results in neutrophils that promote tumor progression

Contact Info

Product

Resources

About