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Abstract Type 2 diabetes mellitus (T2D) is defined by chronic hyperglycemia due to insufficient insulin secretion or activity and decreased insulin sensitivity, known as insulin resistance (IR). This condition leads to oxidative stress and inflammation, increasing the risk of systemic inflammatory diseases. Obesity and a sedentary lifestyle are major risk factors for IR and T2D. Various metabolites act as mediators of IR by disrupting communication between organs. Lipids, including free fatty acids and short-chain fatty acids, along with intracellular lipotoxins, impair insulin function and mitochondrial activity, contributing to IR through direct and indirect mechanisms such as oxidative stress and inflammation. Our research explores the role of TNFα and CXCR1/2 in IR conditions, emphasizing their interactions and potential as therapeutic targets. In this study we selected two models of IR, adipocytes and hepatocytes, since are key players in glucose and lipid metabolism. To develop IR model, TNFα was used as challenge and we focused on investigating the role of CXCR1/2 inhibition. We assessed glucose uptake, insulin signaling pathways, and gene expression related to IR. Cells treated with TNFα showed reduced p-Akt and increased p-JNK levels, indicative of IR. In contrast, CXCR1/2 inhibition restored p-Akt levels and reduced p-JNK levels, suggesting improvements in insulin signaling and glucose uptake. Furthermore, CXCR1/2 inhibition counteracted the TNFα-induced decrease in IGF expression and restored GLUT2 expression, indicating enhanced insulin sensitivity. These results underscore the pivotal role of CXCR1/2 in modulating the inflammatory response and insulin signaling in IR conditions in both IR models. CXCR1/2 inhibition can mitigate IR and improve glucose metabolism. Thus, targeting the TNFα-CXCR1/2 pathway presents a promising therapeutic approach for managing IR and T2D. Further investigation is necessary to understand the clinical implications of these findings and develop effective treatments for patients with IR and T2D.

Abstract Hearing loss impacts the quality of life and affects communication resulting in social isolation and reduced well-being. Despite its impact on society and economy, no therapies for age-related hearing loss are available so far. Loss of mechanosensory hair cells of the cochlea is a common event of hearing loss in humans. Studies performed in birds demonstrating that they can be replaced following the proliferation and transdifferentiation of supporting cells, strongly pointed out on HCs regeneration as the main focus of research aimed at hearing regeneration. Neurotrophins are growth factors involved in neuronal survival, development, differentiation, and plasticity. NGF has been involved in the interplay between auditory receptors and efferent innervation in the cochlea during development. During embryo development, both NGF and its receptors are highly expressed in the inner ears. It has been reported that NGF is implicated in the differentiation of auditory gangliar and hair cells. Thus, it has been proposed that NGF administration can decrease neuronal damage and prevent hearing loss. The main obstacle to the development of hearing impairment therapy is that efficient means of delivery for selected drugs to the cochlea are missing. Herein, in this study NGF was administered by the intranasal route. The first part of the study was focused on a biodistribution study, which showed the effective delivery in the cochlea; while the second part was focused on analyzing the potential therapeutic effect of NGF in senescence-accelerated prone strain 8 mice. Interestingly, intranasal administration of NGF resulted protective in counteracting hearing impairment in SAMP8 mice, ameliorating hearing performances (analyzed by auditory brainstem responses and distortion product otoacoustic emission) and hair cells morphology (analyzed by microscopy analysis). The results obtained were encouraging indicating that the neurotrophin NGF was efficiently delivered to the inner ear and that it was effective in counteracting hearing loss.

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions and plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill patients with COVID-19 compared with patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonists of C5aR1 could be useful for COVID-19 treatment.

Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management.

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in paclitaxel-treated mice, the absence (knock-out mice) or the inhibition of C5aR1 significantly ameliorated CIPN symptoms—in terms of cold and mechanical allodynia—and reduced the chronic pathological state in the paw. Finally, we found that C5aR1 inhibition can counteract paclitaxel-induced anaphylactic cytokine release in macrophages in vitro, as well as the onset of HSRs in mice. Altogether these data identified C5aR1 as a key mediator and a new potential pharmacological target for the prevention and treatment of CIPN and HSRs induced by paclitaxel.

Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hyperalgesic effect. Ex vivo and in vitro studies showed that DF2755A treatment strongly inhibited the expression of CXCR2 agonists, CXCL1/KC, and CXCL5 and of transient receptor potential vanilloid 1 (TRPV1) compared to vehicle, suggesting that its effects can be due to the inhibition of the nociceptive signaling passing through the CXCL1/CXCR1-2 axis and TRPV1. In conclusion, our results highlight the key pathophysiological role played by the CXCL1/CXCR1-2 axis and TRPV1 in the onset and development of peripheral neuropathy in non-Hunner IC and propose DF2755A as a potential therapeutic approach for the treatment of not only inflammatory painful conditions but also neuropathic ones and in particular non-Hunner IC/BPS.

Nerve growth factor (NGF) is the best characterized neurotrophin, and it is known to play an important role in ocular homeostasis. Here, we demonstrated the expression of NGF receptors in adult zebrafish retina and optimized a light-induced retina degeneration (LID) zebrafish model that mimics human cone-rod disorders, demonstrating that intravitreal (IV) administration of rhNGF can boost zebrafish retinal regeneration in this model. Adult zebrafish retinae exposed to 60 h of light irradiation (60 h LID) displayed evident reduction of outer nuclear layer (ONL) thickness and cell number with presence of apoptotic cells. Retinal histologic evaluation at different time points showed that IV therapeutic injection of rhNGF resulted in an increase of ONL thickness and cell number at late time points after damage (14 and 21 days post injury), ultimately accelerating retinal tissue recovery by driving retinal cell proliferation. At a molecular level, rhNGF activated the ERK1/2 pathway and enhanced the regenerative potential of Müller glia gfap- and vim-expressing cells by stimulating at early time points the expression of the photoreceptor regeneration factor Drgal1-L2. Our results demonstrate the highly conserved nature of NGF canonical pathway in zebrafish and thus support the use of zebrafish models for testing new compounds with potential retinal regenerative properties. Moreover, the pro-regenerative effects of IV-injected NGF that we observed pave the way to further studies aimed at evaluating its effects also in mammals, in order to expedite the development of novel rhNGF-based therapeutic approaches for ophthalmological disorders.

A major role for human (h)CXCL8 (interleukin-8) in the pathobiology of myelofibrosis (MF) has been suggested by observations indicating that MF megakaryocytes express increased levels of hCXCL8 and that plasma levels of this cytokine in MF patients are predictive of poor patient outcomes. Here, we demonstrate that, in addition to high levels of TGF-β, the megakaryocytes from the bone marrow of the Gata1low mouse model of myelofibrosis express high levels of murine (m)CXCL1, the murine equivalent of hCXCL8, and its receptors CXCR1 and CXCR2. Treatment with the CXCR1/R2 inhibitor, Reparixin in aged-matched Gata1low mice demonstrated reductions in bone marrow and splenic fibrosis. Of note, the levels of fibrosis detected using two independent methods (Gomori and reticulin staining) were inversely correlated with plasma levels of Reparixin. Immunostaining of marrow sections indicated that the bone marrow from the Reparixin-treated group expressed lower levels of TGF-β1 than those expressed by the bone marrow from vehicle-treated mice while the levels of mCXCL1, and expression of CXCR1 and CXCR2, were similar to that of vehicle-treated mice. Moreover, immunofluorescence analyses performed on bone marrow sections from Gata1low mice indicated that treatment with Reparixin induced expression of GATA1 while reducing expression of collagen III in megakaryocytes. These data suggest that in Gata1low mice, Reparixin reduces fibrosis by reducing TGF-β1 and collagen III expression while increasing GATA1 in megakaryocytes. Our results provide a preclinical rationale for further evaluation of this drug alone and in combination with current JAK inhibitor therapy for the treatment of patients with myelofibrosis.

The intestinal barrier is the main contributor to gut homeostasis. Perturbations of the intestinal epithelium or supporting factors can lead to the development of intestinal hyperpermeability, termed “leaky gut”. A leaky gut is characterized by loss of epithelial integrity and reduced function of the gut barrier, and is associated with prolonged use of Non-Steroidal Anti-Inflammatories. The harmful effect of NSAIDs on intestinal and gastric epithelial integrity is considered an adverse effect that is common to all drugs belonging to this class, and it is strictly dependent on NSAID properties to inhibit cyclo-oxygenase enzymes. However, different factors may affect the specific tolerability profile of different members of the same class. The present study aims to compare the effects of distinct classes of NSAIDs, such as ketoprofen (K), Ibuprofen (IBU), and their corresponding lysine (Lys) and, only for ibuprofen, arginine (Arg) salts, using an in vitro model of leaky gut. The results obtained showed inflammatory-induced oxidative stress responses, and related overloads of the ubiquitin-proteasome system (UPS) accompanied by protein oxidation and morphological changes to the intestinal barrier, many of these effects being counteracted by ketoprofen and ketoprofen lysin salt. In addition, this study reports for the first time a specific effect of R-Ketoprofen on the NFkB pathway that sheds new light on previously reported COX-independent effects, and that may account for the observed unexpected protective effect of K on stress-induced damage on the IEB.

CXCL1, a functional murine orthologue of the human chemokine CXCL8 (IL-8), and its CXCR1 and CXCR2 receptors were investigated in a murine model of acquired epilepsy developing following status epilepticus (SE) induced by intra-amygdala kainate. CXCL8 and its receptors were also studied in human temporal lobe epilepsy (TLE). The functional involvement of the chemokine in seizure generation and neuronal cell loss was assessed in mice using reparixin (formerly referred to as repertaxin), a non-competitive allosteric inhibitor of CXCR1/2 receptors.We found a significant increase in hippocampal CXCL1 level within 24 h of SE onset that lasted for at least 1 week. No changes were measured in blood. In analogy with human TLE, immunohistochemistry in epileptic mice showed that CXCL1 and its two receptors were increased in hippocampal neuronal cells. Additional expression of these molecules was found in glia in human TLE.Mice were treated with reparixin or vehicle during SE and for additional 6 days thereafter, using subcutaneous osmotic minipumps. Drug-treated mice showed a faster SE decay, a reduced incidence of acute symptomatic seizures during 48 h post-SE, and a delayed time to spontaneous seizures onset compared to vehicle controls. Upon reparixin discontinuation, mice developed spontaneous seizures similar to vehicle mice, as shown by EEG monitoring at 14 days and 2.5 months post-SE. In the same epileptic mice, reparixin reduced neuronal cell loss in the hippocampus vs vehicle-injected mice, as assessed by Nissl staining at completion of EEG monitoring.Reparixin administration for 2 weeks in mice with established chronic seizures, reduced by 2-fold on average seizure number vs pre-treatment baseline, and this effect was reversible upon drug discontinuation. No significant changes in seizure number were measured in vehicle-injected epileptic mice that were EEG monitored in parallel.Data show that CXCL1-IL-8 signaling is activated in experimental and human epilepsy and contributes to acute and chronic seizures in mice, therefore representing a potential new target to attain anti-ictogenic effects.

RationaleIncreased IL-8 levels and neutrophil accumulation in the airways are common features found in patients affected by pulmonary diseases such as Asthma, Idiopathic Pulmonary Fibrosis, Influenza-A infection and COPD. Chronic neutrophilic inflammation is usually corticosteroid insensitive and may be relevant in the progression of those diseases.ObjectiveTo explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a significant neutrophilic component.FindingsLadarixin was able to reduce the acute and chronic neutrophilic influx, also attenuating the Th2 eosinophil-dominated airway inflammation, tissue remodeling and airway hyperresponsiveness. Correspondingly, Ladarixin decreased bleomycin-induced neutrophilic inflammation and collagen deposition, as well as attenuated the corticosteroid resistant Th17 neutrophil-dominated airway inflammation and hyperresponsiveness, restoring corticosteroid sensitivity. Finally, Ladarixin reduced neutrophilic airway inflammation during cigarette smoke-induced corticosteroid resistant exacerbation of Influenza-A infection, improving lung function and mice survival.ConclusionCXCR1/2 antagonist Ladarixin offers a new strategy for therapeutic treatment of acute and chronic neutrophilic airway inflammation, even in the context of corticosteroid-insensitivity.

The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of numerous respiratory disorders. The metabolic fate of S-carboxymethyl-L-cysteine is complex. Several clinical studies have demonstrated that the metabolism of this agent differs within the same individual, with sulfur oxygenated metabolites generated upon night-time administration. It has been indicated that this drug behaves like a free radical scavenger and that, in this regard, the sulfide is the active species with sulphoxide metabolites (already oxidized) being inactive. Consequently, a night-time consumption of the drug should be more effective upon daytime administration. Still, this diurnal variation in biotransformation (deactivation) is dependent on the genetic polymorphism on which relies the patient population capacities of S-carboxymethyl-L-cysteine sulphoxidation. It has been reported that those cohorts who are efficient sulfur oxidizers will generate inactive oxygenated metabolites. In contrast, those who have a relative deficiency in this mechanism will be subjected to the active sulfide for a more extended period. In this regard, it is noteworthy that 38–39% of Parkinson’s disease patients belong to the poor sulphoxide cohort, being exposed to higher levels of active sulfide, the active antioxidant metabolite of S-carboxymethyl-L-cysteine. Parkinson’s disease is a neurodegenerative disorder that affects predominately dopaminergic neurons. It has been demonstrated that oxidative stress and mitochondrial dysfunction play a crucial role in the degeneration of dopaminergic neurons. Based on this evidence, in this study, we evaluated the effects of S-carboxymethyl cysteine in an in vitro model of Parkinson’s disease in protecting against oxidative stress injury. The data obtained suggested that an S-carboxymethylcysteine-enriched diet could be beneficial during aging to protect neurons from oxidative imbalance and mitochondrial dysfunction, thus preventing the progression of neurodegenerative processes.

Methionine is an aliphatic, sulfur-containing, essential amino acid that has been demonstrated to have crucial roles in metabolism, innate immunity, and activation of endogenous antioxidant enzymes, including methionine sulfoxide reductase A/B and the biosynthesis of glutathione to counteract oxidative stress. Still, methionine restriction avoids altered methionine/transmethylation metabolism, thus reducing DNA damage and possibly avoiding neurodegenerative processes. In this study, we wanted to study the preventive effects of methionine in counteracting 6-hydroxydopamine (6-OHDA)-induced injury. In particular, we analyzed the protective effects of the amino acid L-methionine in an in vitro model of Parkinson’s disease and dissected the underlying mechanisms compared to the known antioxidant taurine to gain insights into the potential of methionine treatment in slowing the progression of the disease by maintaining mitochondrial functionality. In addition, to ascribe the effects of methionine on mitochondria and oxidative stress, methionine sulfoxide was used in place of methionine. The data obtained suggested that an L-methionine-enriched diet could be beneficial during aging to protect neurons from oxidative imbalance and mitochondrial dysfunction, thus preventing the progression of neurodegenerative processes.

Type 2 diabetes mellitus is a severe public health issue worldwide. It displays a harmful effect on different organs as the eyes, kidneys and neural cells due to insulin resistance and high blood glucose concentrations. To date, the available treatments for this disorder remain limited. Several reports have correlated obesity with type 2 diabetes. Mainly, dysfunctional adipocytes and the regulation of high secretion of inflammatory cytokines are the crucial links between obesity and insulin resistance. Several clinical and epidemiological studies have also correlated the onset of type 2 diabetes with inflammation, which is now indicated as a new target for type 2 diabetes treatment. Thus, it appears essential to discover new drugs able to inhibit the secretion of proinflammatory adipocytokines in type 2 diabetes. Adipocytes produce inflammatory cytokines in response to inflammation or high glucose levels. Once activated by a specific ligand, CXCR1 and CXCR2 mediate some cytokines’ effects by activating an intracellular signal cascade once activated by a specific ligand. Therefore, it is conceivable to hypothesize that a specific antagonist of these receptors may ameliorate type 2 diabetes and glucose metabolism. Herein, differentiated 3T3-L1-adipocytes were subjected to high glucose or inflammatory conditions or the combination of both and then treated with ladarixin, a CXCR1/2 inhibitor. The results obtained point towards the positive regulation by ladarixin on insulin sensitivity, glucose transporters GLUT1 and GLUT4, cytokine proteome profile and lipid metabolism, thus suggesting ladarixin as a potentially helpful treatment in type 2 diabetes mellitus and obesity.

The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.

BackgroundIschemia–reperfusion (IR) is a major contributor to graft rejection after liver transplantation. During IR injury, an intense inflammatory process occurs in the liver. Neutrophils are considered central players in the events that lead to liver injury. CXC chemokines mediate hepatic inflammation following reperfusion. However, few studies have demonstrated in real-time the behavior of recruited neutrophils. We used confocal intravital microscopy (IVM) to image neutrophil migration in the liver and to analyze in real-time parameters of neutrophil recruitment in the inflamed tissue in animals treated or not with reparixin, an allosteric antagonist of CXCR1/2 receptors.Materials and methodsWT and LysM-eGFP mice treated with reparixin or saline were subjected to 60 min of ischemia followed by different times of reperfusion. Mice received Sytox orange intravenously to show necrotic DNA in IVM. The effect of reparixin on parameters of local and systemic reperfusion-induced injury was also investigated.ResultsIR induced liver injury and inflammation, as evidenced by high levels of alanine aminotransferase and myeloperoxidase activity, chemokine and cytokine production, and histological outcome. Treatment with reparixin significantly decreased neutrophil influx. Moreover, reparixin effectively suppressed the increase in serum concentrations of TNF-α, IL-6, and CCL3, and the reperfusion-associated tissue damage. The number of neutrophils in the liver increased between 6 and 24 h of reperfusion, whereas the distance traveled, velocity, neutrophil size and shape, and cluster formation reached a maximum 6 h after reperfusion and then decreased gradually. In vivo imaging revealed that reparixin significantly decreased neutrophil infiltration and movement and displacement of recruited cells. Moreover, neutrophils had a smaller size and less elongated shape in treated mice.ConclusionImaging of the liver by confocal IVM was successfully implemented to describe neutrophil behavior in vivo during liver injury by IR. Treatment with reparixin decreased not only the recruitment of neutrophils in tissues but also their activation state and capacity to migrate within the liver. CXCR1/2 antagonists may be a promising therapy for patients undergoing liver transplantation.

RationaleInfluenza A infections are a leading cause of morbidity and mortality worldwide especially when associated with secondary pneumococcal infections. Inflammation is important to control pathogen proliferation but may also cause tissue injury and death. CXCR1/2 are chemokine receptors relevant for the recruitment of neutrophils. We investigated the role of CXCR1/2 during influenza, pneumococcal, and post-influenza pneumococcal infections.MethodsMice were infected with influenza A virus (IAV) or Streptococcus pneumoniae and then treated daily with the CXCR1/2 antagonist DF2162. To study secondary pneumococcal infection, mice were infected with a sublethal inoculum of IAV then infected with S. pneumoniae 14 days later. DF2162 was given in a therapeutic schedule from days 3 to 6 after influenza infection. Lethality, weight loss, inflammation, virus/bacteria counts, and lung injury were assessed.ResultsCXCL1 and CXCL2 were produced at high levels during IAV infection. DF2162 treatment decreased morbidity and this was associated with decreased infiltration of neutrophils in the lungs and reduced pulmonary damage and viral titers. During S. pneumoniae infection, DF2162 treatment decreased neutrophil recruitment, pulmonary damage, and lethality rates, without affecting bacteria burden. Therapeutic treatment with DF2162 during sublethal IAV infection reduced the morbidity associated with virus infection and also decreased the magnitude of inflammation, lung damage, and number of bacteria in the blood of mice subsequently infected with S. pneumoniae.ConclusionModulation of the inflammatory response by blocking CXCR1/2 improves disease outcome during respiratory influenza and pneumococcal infections, without compromising the ability of the murine host to deal with infection. Altogether, inhibition of CXCR1/2 may be a valid therapeutic strategy for treating lung infections caused by these pathogens, especially controlling secondary bacterial infection after influenza.