Peripheral nerve injuries are clinically common, and the high regenerative capacity is a major advantage of peripheral nerves compared to central nerves. The sciatic nerve is a common site for peripheral nerve injuries, with common causes including iatrogenic intramuscular injection, hip replacements, herniated discs compression, diabetic neuropathy, and chemotherapy-induced peripheral neuropathy, etc (Pham et al., 2011, Wolf et al., 2014, Omarker and Myers, 1998, Callaghan et al., 2012, Baum et al., 2021, Zhang, 2021, Fumagalli et al., 2020). Although sciatic nerve injury does not jeopardize the patient's life, it not only brings serious pathological pain but also causes atrophy in the gastrocnemius muscle, innervated by the nerve, due to long-term nerve injury. This results in nutrient transport disorder and ultimately leading to the patient's motor dysfunction (Yang et al., 2020). This not only reduces the quality of patient’s life but also imposes a serious financial burden on their families. Therefore, it is urgent to find the factors affecting the repair of nerves, promote the repair of damaged nerves, and improve the clinical outcomes of patients.

However, so far, the clinical results of treatment, both in terms of surgical repair and autologous nerve grafting, have been unsatisfactory (Bucan et al., 2019, Su et al., 2022). It is clear that the immune response plays an important role in the regeneration of many tissues (DiPietro, 1995, Chazaud et al., 2009). There are two critical steps in repairing peripheral nerve after injury: first, the removal of axonal and myelin debris to create a favorable microenvironment for injury repair. Second, the regeneration of Schwann cells surrounding the axon. Therefore, Schwann cells and macrophages are the two main cells involved in the post-injury repair (Nocera and Jacob, 2020).

Previous studies have found that macrophages, as intrinsic immune cells, can clear axonal and myelin debris and promote nerve regeneration (Chen et al., 2015, Barrette et al., 2008, Kwon et al., 2013, Niemi et al., 2013, Feng et al., 2023, Kalinski et al., 2020). However, it has also been found that macrophages along with macrophage-derived pro-inflammatory cytokines such as TNF-α, IL-1β, ROS, etc., are closely related to neuropathic pain and other adverse reactions (Leung and Cahill, 2010, Zhu et al., 2021, Jin et al., 2022, Caillaud et al., 2018). Therefore, macrophages have a dual role in nerves, promoting repair while producing pro-inflammatory factors that can be detrimental to nerve repair. It has been found that the phagocytic macrophages are primarily resident macrophages, which start proliferating early after injury and respond quickly before the arrival of blood-derived macrophages (Mueller et al., 2001, Mueller et al., 2003, Hashimoto et al., 2013). Thus, resident macrophages may primarily function as regulatory cells, whereas later arriving blood-borne macrophages may produce inflammatory factors leading to tissue destruction. During inflammation, macrophages release substantial amounts of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), IL-1β, and interleukin-6 (IL-6) (Zhang et al., 2020, Hirano et al., 2017, Xie et al., 2014), leading to an excessive inflammatory response in the injured nerve (Domoto et al., 2021, Conti et al., 2002). An excessive inflammatory response can cause secondary damage, significantly worsening the deficits caused by the initial injury (Schwab and Bartholdi, 1996).

In recent years, studies have shown that chemokines and their receptors play a critical role in regulating immune cell migration and inflammatory responses. Chemokines belong to a superfamily of small peptides that recognize and bind to G protein-coupled receptors on target cells. They can regulate directed migration of immune cells under pathological conditions, contribute to tumorigenesis and metastasis, and influence a variety of immune responses that occur after bacterial infection (Sokol and Luster, 2015, Chow and Luster, 2014, Domingo-Gonzalez et al., 2016). CXCL1 is a significant chemokine among the more than forty chemokines identified to date. It plays a crucial role in various inflammatory diseases by recruiting a wide range of immune cells through binding to its receptor, CXCR2 (Korbecki et al., 2022a, Korbecki et al., 2022b). While previous studies have primarily focused on neutrophil migration, there has been limited attention given to macrophage migration. It has been observed that macrophages also express CXCR2 receptors on their surface (Liu et al., 2021). For example, the increase of macrophages in damaged myocardium, human distal nerve pain due to human immunodeficiency virus type 1 (HIV-1), retinal vascular damage and retinopathy due to hypertension. All these instances are related to macrophages recruited by the CXCL1-CXCR2 pathway (Wang et al., 2018, Wang et al., 2022, Ntogwa et al., 2020). The above data suggest that the ability of macrophages migrating to lesion sites is involved in the development and progression of many diseases, largely influenced by the chemokine CXCL1 and its receptor CXCR2.

Previous studies have found that macrophages are recruited to the site of injury after peripheral nerve injury by the chemokine C-C motif chemokine ligand 2 (CCL) 2 secreted by Schwann cells, which attracts them by binding to the macrophage surface receptor C-C motif chemokine receptor (CCR) 2 (Zigmond and Echevarria, 2019). However, there are other studies found that in the absence of CCL2, macrophages can be recruited vicariously to the site of injury through other pathways such as CCL7, CCL12 (Talsma et al., 2022). Thus, there may be multiple pathways for macrophage recruitment, and how macrophages are recruited after sciatic nerve injury has not been specifically studied. It has been reported that sciatic nerve injury leads to increased CXCL1 expression in the nerve, but its source is unclear (Manjavachi et al., 2014, Lindborg et al., 2017). Considering that CXCL1 and CXCR2 have chemotactic effects upon binding, we hypothesized that macrophage recruitment after sciatic nerve injury might be related to the CXCL1-CXCR2 pathway. Therefore, the starting point of this study was to explore the macrophage recruitment pathway after sciatic nerve injury using SB225002 and investigate the pathways through which recruited macrophages promote the production and release of inflammatory factor. The discovery of key components in the regulatory pool of inflammasome to control excessive inflammation and provide a favorable repair environment for injured nerves may pave the way for the development of therapeutic strategies for nerves injuries.