CXCL1-CXCR2 axis mediates inflammatory response after sciatic nerve injury by regulating macrophage infiltration.

Macrophages play a crucial role in the inflammatory response following sciatic nerve injury. Studies have demonstrated that C-X-C motif chemokine (CXCL) 1 recruit macrophages by binding to C-X-C chemokine receptor (CXCR) 2 and participates in the inflammatory response of various diseases. Based on these findings, we aimed to explore the role of the CXCL1-CXCR2 axis in the repair process after peripheral nerve injury. Initially, we simulated sciatic nerve injury and observed an increased expression of CXCL1 and CXCR2 in the nerves of the injury group. Both in vivo and in vitro experiments confirmed that the heightened CXCL1 expression occurs in Schwann cells and is secreted, while the elevated CXCR2 is expressed by recruited macrophages. In addition, in vitro experiments demonstrated that the binding of CXCL1 to CXCR2 can activate the NLRP3 inflammasome and promote the production of interleukin-1 beta (IL-1ß) in macrophages. However, after mice were subjected to sciatic nerve injury, the number of macrophages and the expression of inflammatory factors in the sciatic nerve were reduced following treatment with the CXCR2 inhibitor SB225002. Simultaneously, we evaluated the sciatic nerve function index, the expression of p75 neurotrophic factor receptor (p75NTR), and myelin proteins, and all of these results were improved with the use of SB225002. Thus, our results suggest that after sciatic nerve injury, the CXCL1-CXCR2 axis mediates the inflammatory response by promoting the recruitment and activation of macrophages, which is detrimental to the repair of the injured nerves. In contrast, treatment with SB225002 promotes the repair of injured sciatic nerves.

Pathogenic Th17 cell-mediated liver fibrosis contributes to resistance to PD-L1 antibody immunotherapy in hepatocellular carcinoma.

Understanding the mechanisms of resistance of hepatocellular carcinoma (HCC) to targeted therapies and immune checkpoint blockade is critical for the development of new combination therapies and improving patient survival. Here, we found that in HCC, anti-programmed cell death 1 ligand 1 (PD-L1) therapy reduces liver cancer growth, but the tumors eventually become resistant to continued therapy. Experimental analyses shows that the infiltration of pathogenic T helper 17 (pTh17) cells increases in drug-resistant HCC, and pTh17 cells secrete interleukin-17A (IL-17A), which promotes the expression of PD-L1 on the surface of HCC cells and produces resistance to anti-PD-L1 therapy. Anti-IL-17A combined with PD-L1 blockade significantly increased the infiltration of cytotoxic CD8+ T cells expressing high levels of interferon-γ and reduced treatment resistance in HCC. These results support the combination of anti-PD-L1 and anti-IL-17A as a novel strategy to induce effective T cell-mediated anti-tumor immune responses.

IL-17A functions and the therapeutic use of IL-17A and IL-17RA targeted antibodies for cancer treatment.

Interleukin 17A (IL-17A) is a major member of the IL-17 cytokine family and is produced mainly by T helper 17 (Th17) cells. Other cells such as CD8+ T cells, γδ T cells, natural killer T cells and innate lymphoid-like cells can also produce IL-17A. In healthy individuals, IL-17A has a host-protective capacity, but excessive elevation of IL-17A is associated with the development of autoimmune diseases and cancer. Monoclonal antibodies (mAbs) targeting IL-17A (e.g., ixekizumab and secukinumab) or IL-17A receptor (IL-17RA) (e.g., brodalumab) would be investigated as potential treatments for these diseases. Currently, the application of IL-17A-targeted drugs in autoimmune diseases will provide new ideas for the treatment of tumors, and its combined application with immune checkpoint inhibitors has become a research hotspot. This article reviews the mechanism of action of IL-17A and the application of anti-IL-17A antibodies, focusing on the research progress on the mechanism of action and therapeutic blockade of IL-17A in various tumors such as colorectal cancer (CRC), lung cancer, gastric cancer and breast cancer. Moreover, we also include the results of therapeutic blockade in the field of cancer as well as recent advances in the regulation of IL-17A signaling.

The role of CXCL1/CXCR2 axis in neurological diseases.

The C-X-C chemokine ligand (CXCL) 1 and its receptor C-X-C chemokine receptor (CXCR) 2 are widely expressed in the peripheral nervous systems (PNS) and central nervous systems (CNS) and are involved in the development of inflammation and pain after various nerve injuries. Once a nerve is damaged, it affects not only the neuron itself but also lesions elsewhere in its dominant site. After the CXCL1/CXCR2 axis is activated, multiple downstream pathways can be activated, such as c-Raf/MAPK/AP-1, p-PKC-µ/p-ILK/NLRP3, JAK2/STAT3, TAK1/NF-κB, etc. These pathways in turn mediate cellular motility state or cell migration. CXCR2 is expressed on the surface of neutrophils and monocytes/macrophages. These cells can be recruited to the lesion through the CXCL1/CXCR2 axis to participate in the inflammatory response. The expression of CXCR2 in neurons can activate some pathways in neurons through the CXCL1/CXCR2 axis, thereby causing damage to neurons. CXCR2 is also expressed in astrocytes, and when CXCR2 activated, it increases the number of astrocytes but impairs their function. Since inflammation can occur at almost any site of injury, elucidating the mechanism of CXCL1/CXCR2 axis' influence on inflammation may provide a favorable target for clinical treatment. Therefore, this article reviews the research progress of the CXCL1/CXCR2 axis in neurological diseases, aiming to provide a more meaningful theoretical basis for the treatment of neurological diseases.